CN1711258A

CN1711258A - Pyrimidine compounds

Info

Publication number: CN1711258A
Application number: CNA2003801033182A
Authority: CN
Inventors: 王淑东; 克里斯托弗·米德斯; 加文·伍德; 贾尼丝·奥博伊尔; 坎贝尔·麦金尼斯; 彼得·费希尔
Original assignee: Cyclacel Ltd
Current assignee: Cyclacel Ltd
Priority date: 2002-11-14
Filing date: 2003-11-14
Publication date: 2005-12-21
Anticipated expiration: 2023-11-14
Also published as: WO2004043953A1; PT1567522E; EP1567522B1; US20050192300A1; CA2502190A1; EP1864983A1; US7432260B2; AU2003301977A1; BR0316152A; US7897605B2; EP1567522A1; ES2293094T3; JP2006514619A; DK1567522T3; ATE373653T1; CY1106933T1; US20080287439A1; CN100415740C; JP4681880B2; NZ539670A

Abstract

The present invention relates to substituted pyrimidines of formula (I), their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent kinases (CDKs) and hence their use in the treatment of proliferative disorders and/or viral disorders.

Description

Pyrimidine compound

The present invention relates to that new 2-replaces-4-heteroaryl-pyrimidine derivative with and purposes in treatment. More specifically, the present invention relates to have the 2-that improves solubility property replaces-4-heteroaryl-pyrimidine derivative.

Background of invention

We disclosed in the past that 2-replaces-4-heteroaryl-pyrimidine with and purposes (Fischer PM, Wang S.PCT Intl.Patent Appl.Publ.WO 01/072745 in the treatment proliferative disease; Cyclacel Limited, UK, 2001). These compounds suppress cyclin-deopendent protein kinase (CDKs), especially CDK4/ cyclin D, CDK2/ cyclin E, CDK2/ cyclin A and CDK1/ cyclin B, i.e. important multienzyme complex in people's cell cycle progression. In addition, 2-phenyl amino-4-heteroaryl-pyrimidine has in the body and external optionally anti-proliferative activity (Wang S, Blake D to people's tumour cell widely, Clarke R, Duff S, McClue SJ, McInnes C, Melville J, Stewart K, Taylor P, Westwood R, Wood G, Wu S-Y, Zhelev NZ, Zheleva DI, Walkinshaw M, Lane DP, Fischer PM.Proc.Amer.Assoc.Cancer Res.2002; 43:4202).

The present invention seek to provide other 2-replaces-4-heteroaryl-pyrimidine compound. More specifically, the present invention preferably seek to provide the 2-that shows improved solubility and/or bioavilability replaces-4-heteroaryl-pyrimidine compound.

Summary of the invention

First aspect present invention relates to formula I compound or pharmaceutically acceptable salt thereof,

Wherein:

(A)X ¹And X²One of be S, and X¹And X²In another is N;

" a " is singly-bound;

" b ", " c ", " d ", " e " and " f " be single or two keys to form the thiazole basic ring;

R ²Independently together as following to R¹、R ^3-8Definition; Or

(B)X ¹And X²One of be S, and X¹And X²In another is NR¹⁷；

" a " and " d " respectively is two keys;

" b ", " c ", " e " and " f " respectively are singly-bound;

R ²Be oxo group; And

R ¹⁷Be H or alkyl;

Wherein:

Z is NH, NHCO, NHSO₂、NHCH ₂、CH ₂、CH ₂CH ₂、CH＝CH、SO ₂Or SO;

R ¹、R ³、R ⁴、R ⁵、R ⁶、R ⁷And R⁸H, alkyl, alkyl-R independently of one another⁹, aryl, aryl-R⁹, aralkyl, aralkyl-R⁹, halogen, NO₂, CN, OH, O-alkyl, COR⁹、COOR ⁹, O-aryl, O-R⁹、NH ₂, NH-alkyl, NH-aryl, N-(alkyl)₂, N-(aryl)₂, N-(alkyl) (aryl), NH-R⁹、N-(R ⁹)(R ¹⁰), N-(alkyl) (R⁹), N-(aryl) (R⁹)、COOH、CONH ₂, CONH-alkyl, CONH-aryl, CON-(alkyl) (R⁹), CON (aryl) (R⁹)、CONH-R ⁹、 CON-(R ⁹)(R ¹⁰)、SO ₃H、SO ₂-alkyl, SO₂-alkyl-R⁹、SO ₂-aryl, SO₂-aryl-R⁹、 SO ₂NH ₂、SO ₂NH-R ⁹、SO ₂N-(R ⁹)(R ¹⁰)、CF ₃, CO-alkyl, CO-alkyl-R⁹, CO-aryl, CO-aryl-R⁹Or R¹¹, wherein alkyl, aryl, aralkyl can further be selected from halogen, NO by one or more₂, OH, O-methyl, NH₂、COOH、CONH ₂And CF₃Group replace;

R wherein¹、R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷And R⁸In at least one for containing R⁹Or R¹⁰Group, or be R¹¹；

R ⁹And R¹⁰Be solubilizing group independently of one another, be selected from:

(i)-single-, two-or polyhydroxylated alicyclic group;

-two-or polyhydroxylated aliphatic or aromatic group;

-carbohydrate derivative;

-contain O-and/or S heterocyclic radical, optionally replaced by one or more hydroxyl;

-aliphatic or aromatic group comprise acid amides, Ya Sulfone, Sulfone or sulfonamide functional group; Or

-halogenated alkyl carbonyl;

(ii)COOH、SO ₃H、OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

(iii) Y, wherein Y is selected from alicyclic, fragrance or heterocyclic radical, comprise functional group=N-,-O-,-NH2 ,-one or more in NH-, quaternary amine, guanidine and the amidine, the wherein optional one or more substituting groups replacements that are selected from the following group of Y:

-SO ₂-alkyl;

-alkyl, optional by one or more OH group replacement;

-CO-alkyl;

-aralkyl;

-COO-alkyl; And

-ether, optional by one or more OH group replacement; And

Wherein Y is not pyridine radicals;

(iv) natural or non-natural amino acid, peptide or peptide derivative;

Each R¹¹For as above-mentioned for R⁹And R¹⁰(i) in the definition or solubilizing group (iv); Or be selected from:

(v)OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

(vi) Y as defined above, but be not guanidine and quaternary amine;

(vii)NHCO(CH ₂) _m[NHCO(CH ₂) _m’] _p[NHCO(CH ₂) _m”] _qY or NHCO (CH₂) _tNH(CH ₂) _t’Y, wherein p and q respectively are 0 or 1, and m, m ', m ", t and t ' be from 1 to 10 integer independently of one another; And

(viii)(CH ₂) _nNR ¹⁴COR ¹²、(CH ₂) _n’NR ₁₅SO ₂R ¹³Or SO₂R ¹⁶, R wherein¹²、R ¹³And R¹⁶Respectively doing for oneself to choose wantonly comprises one or more heteroatomic alkyl, and it is optional by one or more OH, NH of being selected from₂, halogen and NO₂Substituting group replace R¹⁴And R¹⁵Be H or alkyl independently of one another, and n and n ' are 0,1,2 or 3 independently of one another;

(ix) ether or polyethers, optional by one or more hydroxyl or the replacement of one or more Y group;

(x)(CH ₂) _rNH ₂ Wherein r is 0,1,2 or 3;

(xi)(CH ₂) _r’OH; Wherein r ' is 0,1,2 or 3;

Condition is that described compound is not:

2-chloro-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-acetamide;

N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-Methanesulfomide;

2-chloro-N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide;

3-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-methyl alcohol;

2-{4-[4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-ethanol; Or

2-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-ethanol.

Second aspect present invention relates to a kind of pharmaceutical composition, comprises as defined above formula I compound and pharmaceutically acceptable diluent, excipient or carrier.

Third aspect present invention relates to formula I compound as defined above for the preparation of the purposes in the medicine for the treatment of proliferative disease.

Fourth aspect present invention relates to formula Ia compound or pharmaceutically acceptable salt thereof, for the preparation of the treatment viral disease medicine in purposes,

Wherein:

(A)X ¹And X²One of be S, and X¹And X²In another is N;

" a " is singly-bound;

R ²Independently together as following to R¹、R ^3-8Definition; Or

(B)X ¹And X²One of be S, and X¹And X²In another is NR¹⁷；

" a " and " d " respectively is two keys;

" b ", " c ", " e " and " f " respectively are singly-bound;

R ²Be oxo group; And

R ¹⁷Be H or alkyl;

Wherein:

(i)-single-, two-or polyhydroxylated alicyclic group;

-two-or polyhydroxylated aliphatic or aromatic group;

-carbohydrate derivative;

-halogenated alkyl carbonyl;

(ii)COOH、SO ₃H、OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

(iii) Y, wherein Y is selected from alicyclic, fragrance or heterocyclic radical, comprise functional group=N-,-O-,-NH₂One or more in ,-NH-, quaternary amine, guanidine and the amidine, the wherein optional one or more substituting groups replacements that are selected from the following group of Y:

-SO ₂-alkyl;

-alkyl, optional by one or more OH group replacement;

-CO-alkyl;

-aralkyl;

-COO-alkyl; And

-ether, optional by one or more OH group replacement; And

Wherein Y is not pyridine radicals;

(iv) natural or non-natural amino acid, peptide or peptide derivative;

(v)OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

(vi) Y as defined above, but be not guanidine and quaternary amine;

(viii)(CH ₂) _nNR ¹⁴COR ¹²、(CH ₂) _n’NR ¹⁵SO ₂R ¹³Or SO₂R ¹⁶, R wherein¹²、R ¹³And R¹⁶Respectively doing for oneself to choose wantonly comprises one or more heteroatomic alkyl, and it is optional by one or more OH, NH of being selected from₂, halogen and NO₂In substituting group replace R¹⁴And R¹⁵Be H or alkyl independently of one another, and n and n ' are 0,1,2 or 3 independently of one another;

(x)(CH ₂) _rNH ₂ Wherein r is 0,1,2 or 3;

(xi)(CH ₂) _r’OH; Wherein r ' is 0,1,2 or 3.

Fifth aspect present invention relates to the as defined above kinase whose purposes of formula I compound CKIs.

Sixth aspect present invention relates to the as defined above purposes of formula I compound in the analysis that can suppress the kinase whose candidate compound of cyclin dependence for the identification of other.

Describe in detail

Term used herein " alkyl " comprises side chain and the straight chained alkyl of existing 1～8 carbon atom, such as methyl, ethyl propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, hexyl etc., and term " low alkyl group " similarly is used for the group that expression has 1～4 carbon atom.

(single-or many-) that term used herein " aryl " refers to replace or unsubstituted single fragrance or many aroma systems, wherein said many aroma systems can be condense or uncondensed. Preferably, term " aryl " comprises the group with 6～10 carbon atoms, such as phenyl, naphthyl etc. Term " aryl " and term " fragrance " synonym.

Term " aralkyl " is the term alkyl that as above provides and the conjunction of aryl.

The aliphatic group of term " alicyclic " finger ring shape.

Term " aliphatic " get the common implication of the art and comprise non--aromatic group such as alkane, alkene and alkynes with and the derivative that replaces.

Term used herein " carbohydrate derivative " refers to general formula C_x(H ₂O) _yThe compound or derivatives thereof. Preferably, described carbohydrate be single-, two-or trisaccharide. Monose can straight chain or ring molecule, and classifies according to the carbon atom number that it has; Triose has 3 carbon atoms, and tetrose has 4 carbon atoms, and pentose has 5 carbon atoms, and hexose has 6 carbon atoms. These secondary groups can further be divided into aldose and ketose, depend on and whether comprise aldehyde radical in the molecule (CHO) or ketone group (C=O). The representative instance of monose comprises glucose, fructose and galactolipin. Disaccharides is by two continuous monose molecular compositions, and for example comprises maltose and lactose. Trisaccharide is by three continuous monose molecular compositions.

Term used herein " derivative " comprises the chemical modification of entity. The example that exemplifies of described chemical modification is that hydrogen is by halogen, alkyl, acyl group or amino the replacement.

Term " heterocycle " refers to comprise one or more heteroatomic saturated or unsaturated cyclic groups in ring.

Phrase used herein " preparation of medicine " comprise with formula I compound directly as the purposes of medicine with and in the purposes of the antivirotic screening process (screening programme) that is used for other or in the purposes in any stage of the preparation of described medicine.

In a preferred embodiment, the present invention relates to formula Ib compound or pharmaceutically acceptable salt thereof,

X wherein¹And X²One of be S, X¹And X²In another be N, and Z, R^1-8As above definition.

In another preferred embodiment, the present invention relates to formula Ic compound or pharmaceutically acceptable salt thereof,

Wherein

X ¹And X²One of be S, X¹And X²In another be N;

R ¹、R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷And R⁸H, alkyl, alkyl-R independently of one another⁹, aryl, aryl-R⁹, aralkyl, aralkyl-R⁹, halogen, NO₂, CN, OH, O-alkyl, COR⁹、 COOR ⁹, O-aryl, O-R⁹、NH ₂, NH-alkyl, NH-aryl, N-(alkyl)₂, N-(aryl)₂, N-(alkyl) (aryl), NH-R⁹、N-(R ⁹)(R ¹⁰), N-(alkyl) (R⁹), N-(aryl) (R⁹)、COOH、 CONH ₂, CONH-alkyl, CONH-aryl, CON-(alkyl) (R⁹), CON (aryl) (R⁹)、 CONH-R ⁹、CON-(R ⁹)(R ¹⁰)、SO ₃H、SO ₂-alkyl, SO₂-alkyl-R⁹、SO ₂-aryl, SO₂-aryl-R⁹、SO ₂NH ₂、SO ₂NH-R ⁹、SO ₂N-(R ⁹)(R ¹⁰)、CF ₃, CO-alkyl, CO-alkyl-R⁹, CO-aryl, CO-aryl-R⁹Or R¹¹, wherein alkyl, aryl, aralkyl can further be selected from halogen, NO by one or more₂, OH, O-methyl, NH₂、COOH、CONH ₂And CF₃Group replace;

(i)-single-, two-or polyhydroxylated alicyclic group;

-two-or polyhydroxylated aliphatic or aromatic group;

-carbohydrate derivative;

-halogenated alkyl carbonyl;

(ii)COOH、SO ₃H、OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

-SO ₂-alkyl;

-alkyl, optional by one or more OH group replacement;

-CO-alkyl;

-aralkyl;

-COO-alkyl; And

-ether, optional by one or more OH group replacement; And

Wherein Y is not pyridine radicals;

(iv) natural or non-natural amino acid, peptide or peptide derivative;

(v)OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

(vi) Y as defined above, but be not guanidine and quaternary amine;

(vii)NHCO(CH ₂) _m[NHCO(CH ₂) _m’] _p[NHCO(CH ₂) _m”] _qY, wherein p and q respectively are 0 or 1, and m, m ' and m " from 1 to 10 the integer of respectively doing for oneself; And

(viii)NHCOR ¹²Or NHSO₂R ¹³, R wherein¹²And R¹³Respectively doing for oneself to choose wantonly comprises one or more heteroatomic alkyl, and it is optional by one or more OH, NH of being selected from₂, halogen and NO₂Substituting group replace;

(ix) ether or polyethers optional are replaced by one or more hydroxyl;

Condition is that described compound is not:

2-chloro-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-acetamide; Or

2-chloro-N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide.

Preferably, formula I compound is with single-or two-thiazole of replacing-3-base or thiazole-5-base, and described group is connected to pyrimidine ring by a ring carbon atom. More preferably, described heterocycle is thiazole-5-base.

Therefore, in a preferred embodiment of the present invention, X¹Be S and X²Be N.

Following preferred feature is applicable to formula I, Ia, Ib and Ic compound.

In another preferred embodiment, Z is NH.

In another preferred embodiment, R³Be H.

In another preferred embodiment, R²、R ⁵、R ⁶Or R⁷In at least one for containing R⁹Or R¹⁰Group or be R¹¹。

In an especially preferred embodiment, X¹Be S, X²Be N, Z is NH, R¹Be Me, R²Be alkyl or amino, R³Be H, R⁵、R ⁶And R⁷In one or two be CF₃, OH, O-alkyl, halogen, NO₂、NH ₂, NH-alkyl or N-(alkyl)₂, and R²、R ⁵、R ⁶Or R⁷In at least one for containing R⁹Or R¹⁰Group or be R¹¹。

In another preferred embodiment, R¹、R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷And R⁸In at least one is R¹¹。

In a preferred embodiment, R¹¹For as above-mentioned for R⁹And R¹⁰(i)-(iv) in the definition or (v)-(x) defined solubilizing group.

In another preferred embodiment, R¹¹For as above-mentioned for R⁹And R¹⁰(i)-(iv) in the definition or (v)-(vii), (ix)-(x) defined solubilizing group or be selected from:

-(CH ₂) _nNR ¹⁴COR ¹², R wherein¹²Comprise one or more heteroatomic alkyl for optional, and described group is optional by one or more OH, NH of being selected from₂And NO₂Substituting group replace,

-(CH ₂) _n’NR ¹⁵SO ₂R ¹³, R wherein¹³Comprise one or more heteroatomic alkyl for optional, and described group is optional by one or more OH, NH of being selected from₂, halogen and NO₂Substituting group replace,

-SO ₂R ¹⁶, R wherein¹⁶Comprise one or more heteroatomic alkyl for optional, and described group is optional by one or more OH, NH of being selected from₂, halogen and NO₂Substituting group replace;

And

R ¹⁴And R¹⁵Be H or alkyl independently of one another, and n and n ' are 0,1,2 or 3 independently of one another.

Preferably, described solubilizing group is R¹¹And be:

(a) Y as defined above, but get rid of guanidine, wherein Y also can be and comprises one or more=alicyclic, fragrance or the heterocyclic radical of N-group;

(b)NHCO(CH ₂) _m[NHCO(CH ₂) _m’] _p[NHCO(CH ₂) _m”] _qY or NHCO (CH₂) _tNH(CH ₂) _t’Y, wherein p and q respectively are 0 or 1, and m, m ', m ", respectively do for oneself from 1 to 10 integer of t and t '; Or

(c)(CH ₂) _nNR ¹⁴COR ¹²、(CH ₂) _n’NR ¹⁵SO ₂R ¹³Or SO₂R ¹⁶, R wherein¹²、R ¹³And R¹⁶Respectively doing for oneself to choose wantonly comprises one or more heteroatomic alkyl, and described group is optional by one or more OH, NH of being selected from₂, halogen and NO₂Substituting group replace R¹⁴And R¹⁵Be H or alkyl independently of one another, and n and n ' are 0,1,2 or 3 independently of one another.

Preferably, described solubilizing group is R¹¹, and R¹¹Be:

(b)NHCO(CH ₂) _m[NHCO(CH ₂) _m’] _p[NHCO(CH ₂) _m”] _qY, wherein p and q respectively are 0 or 1, and m, m ', m ", respectively do for oneself from 1 to 10 integer of t and t ';

(c)NHCOR ¹²Or NHSO₂R ¹³, R wherein¹²And R¹³Respectively doing for oneself to choose wantonly comprises one or more heteroatomic alkyl, and described group is optional by one or more OH, NH of being selected from₂, halogen and NO₂Substituting group replace.

Even more preferably, Y is for comprising functional group-O-, NH₂,-NH-,=one or more alicyclic group in N-, quaternary amine or the amidine, and wherein Y is optional is replaced by one or more substituting groups as defined above.

More preferably, Y is morpholine or piperazine, and each group is optional by one or more SO that are selected from₂-alkyl, optional alkyl, CO-alkyl, aralkyl, COO-alkyl and the optional ether that is replaced by one or more OH group that is replaced by one or more OH group.

In particularly preferred embodiment of the present invention, Y is 2-oxo-six hydrogen-thieno [3,4-d] imidazole radicals.

In a preferred embodiment, R²、R ⁶Or R⁷In at least one is R¹¹。

For this embodiment, preferably R¹¹Be selected from following group:

CH ₂CH ₂OH SO ₂Me CH ₂OH CH ₂NH ₂

In an especially preferred embodiment, R⁶Or R⁷Be R¹¹ More preferably, R⁶Be R¹¹And R²、R ⁴、R ⁵、R ⁷And R⁸Be selected from independently of one another alkyl, H, CF₃, OH, O-alkyl, halogen, NO₂、NH ₂, NH-alkyl and N-(alkyl)₂ More preferably, R⁶Be R¹¹And R²、R ⁴、R ⁵、 R ⁷And R⁸Be selected from independently of one another alkyl, H, O-alkyl, halogen, NO₂、NH ₂With the NH-alkyl. Even more preferably, R⁶Be R¹¹And R⁴、R ⁵、R ⁷And R⁸All be H and R²Be selected from alkyl, O-alkyl, NH₂With the NH-alkyl.

Even more preferably, for this embodiment, R¹¹Be selected from:

SO ₂MeCH ₂CH ₂OH

In another preferred embodiment, R⁷Be R¹¹And R⁴、R ⁵、R ⁶、R ⁸All be H, and R²Be selected from alkyl, O-alkyl, NH₂With the NH-alkyl. Preferably, for this embodiment, R¹¹Be selected from:

SO ₂MeCH ₂OHCH ₂NH ₂

In another preferred embodiment of the present invention, R²Or R⁶In at least one is R¹¹。

For this embodiment, R¹¹Preferably be selected from following group:

In an especially preferred embodiment, R⁶Be R¹¹。

For this embodiment, wherein R⁶Be R¹¹, R preferably²、R ⁴、R ⁵、R ⁷And R⁸Be selected from independently of one another alkyl, H, CF₃, OH, O-alkyl, halogen, NO₂、NH ₂, NH-alkyl and N-(alkyl)₂。

Even more preferably, R²、R ⁴、R ⁵、R ⁷And R⁸Be selected from independently of one another alkyl, H, O-alkyl, halogen, NO₂、NH ₂With the NH-alkyl.

More preferably, R⁴、R ⁵、R ⁷And R⁸All be H and R²Be selected from alkyl, O-alkyl, NH₂With the NH-alkyl.

More preferably, R¹¹Be selected from:

In substituting preferred embodiment, R²Be R¹¹。

For this embodiment, R²Be R¹¹, R preferably⁴、R ⁵、R ⁶、R ⁷And R⁸Be selected from independently of one another alkyl, H, CF₃, OH, O-alkyl, halogen, NO₂、NH ₂, NH-alkyl and N-(alkyl)₂。

More preferably, R⁴、R ⁵、R ⁶、R ⁷And R⁸Be selected from independently of one another H, O-alkyl, halogen, N-(alkyl)₂、NO ₂。

More preferably, R⁵Or R⁷One of be selected from NO₂, alkoxyl, halogen and N-(alkyl)₂, and R⁴、R ⁵、R ⁶、R ⁷And R⁸In other groups all be H.

More preferably, R¹¹Be selected from:

In preferred embodiment of the present invention, R¹Be methyl, Z is NH and R³Be H.

In another embodiment, described the compounds of this invention is formula Id compound or pharmaceutically acceptable salt thereof,

Preferably, R¹And R^3-8For as above-mentioned for the definition in formula I, Ia, Ib and the Ic compound. Preferably, R¹⁷Be alkyl, more preferably methyl.

In preferred embodiment of the present invention, formula I compound is selected from compound listed in table 1, but gets rid of compound [24], [32] and [33].

In an especially preferred embodiment, formula I compound is selected from following compound:

[4-(2-methoxyl group-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine;

[4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine;

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine;

[4-(2-N-methylamino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholino phenyl)-amine;

[4-(2-ethyl amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine;

1-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-ethyl ketone;

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-piperazine-1-base-phenyl)-amine;

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[4-(4 '-2 "-the ethoxy ethanol piperazinyl)-phenyl]-amine;

3-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-third-1-alcohol;

2-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-ethanol;

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[4-(4-mesyl-piperazine-1-yl)-phenyl]-amine;

[4-(4-benzyl-piperazine-1-yl)-phenyl]-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-yl]-amine;

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine;

[4-(2-methoxyl group-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine;

3-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide;

(2S)-2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide;

(2R, 3R)-2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide;

(2R)-2-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide;

(2S, 3S)-2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide;

4-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide;

3-amino-N-{4-methyl-5-[2-(4-morpholine-4-base-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide;

3-bromo-N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide;

N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-morpholine-4-base-propionamide;

N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-3-morpholine-4-base-propionamide;

N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-3-(4-methyl-piperazine-1-yl)-propionamide;

2-chloro-N-{5-[2-(3-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide;

2-chloro-N-{5-[2-(3-methoxyl group-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide;

2-chloro-N-{5-[2-(4-dimethylamino-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide;

4-(4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-base carbamoyl }-methyl)-piperazine-1-carboxylic acid tert-butyl group ester;

N-{5-[2-(4-dimethylamino-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-2-[2-(2-hydroxyl-ethyoxyl)-ethyl is amino]-acetamide;

6-[5-(2-oxo-six hydrogen-thieno [3,4-d] imidazoles-4-yl)-valeryl is amino]-caproic acid (2-{4-methyl-5-[2-(4-morpholine-4-base-phenyl amino)-pyrimidine-4-yl]-thiazole-2-base carbamoyl }-ethyl)-acid amides;

N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-Methanesulfomide;

3-bromo-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide;

3-(1-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperidines-4-yl)-third-1-alcohol;

2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide; And

2-chloro-N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide.

In another preferred embodiment of the present invention, described compound formula I is selected from following compound:

(2R)-2-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide; And

N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-3-morpholine-4-base-propionamide.

In a preferred embodiment, the compound of formula I can show anti-hyperplasia effect in the human cell line, as utilizes 72 hours MTT cytotoxicity analysis of standard to measure. Preferably, with described MTT analysis to measure, the IC of the compound exhibits of formula I₅₀Value is less than 10 μ M, more preferably less than 5 μ M, even more preferably less than 1 μ M, more preferably, the compound of formula I is selected from following compound: [4], [8], [12], [14], [16], [22], [24], [25], [29], [32], [33], [39], [40], [50], [53], [61], [57], [62], [63], [64], [65] and [77]. More preferably, the IC of described compound exhibits₅₀Value is less than 0.5 μ M, more preferably less than 0.2 μ M. Even more preferably, described compound is selected from following compound: [24], [25], [32], [33], [50], [62] and [64].

In another preferred embodiment, the compound of formula I is selected from [1], [11], [15] and [16].

In another preferred embodiment, the compound of formula I can suppress one or more protein kinase, as utilizes the analysis to measure of describing in the embodiment part to obtain. Preferably, the IC of the compound exhibits of formula I₅₀Value is less than 10 μ M, more preferably less than 5 μ M, even more preferably less than 1 μ M or less than 0.5 μ M, more preferably less than 0.1 μ M. More preferably, the compound of formula I is selected from following compound: [11], [13], [14], [15], [20], [21], [22], [24], [25], [32], [50], [53], [54], [55], [56], [57], [59], [61], [62], [64], [68], [71], [82], 83], [84] and [85]. More preferably, described compound exhibits is less than the IC of 0.01 μ M₅₀Value. Even more preferably, described compound is selected from following compound: [11], [22], [24], [32], [50], [62], [71] and [85].

In another preferred embodiment, the compound of formula I is selected from [1], [3], [11], [15] and [16].

The invention provides on phenyl of some row 2-phenyl amino-4-heteroaryl-pyrimidine systems and/or the heteroaryl ring compound with solubilising functional group. Utilize the modification of solubilising part to keep the Bioactivity (CDKs to people's cell of transforming suppresses and cytotoxicity) of needs also to cause in some cases the increase of amazing and beat all effectiveness. In addition, utilize the solubilising strategy that provides here, absorption and especially oral administration biaavailability also improve in the body.

The treatment purposes

Therefore having been found that formula I compound has antiproliferative activity and believes can be used for treating proliferative disease such as cancer, leukaemia and other the disease relevant with uncontrolled cell proliferation such as psoriasis and ISR. As definition here, antiproliferative activity in the scope of the invention can be confirmed by the activity that suppresses cell proliferation in external full cell analysis, for example utilizes clone AGS, H1299 or SJSA-1 or is confirmed by the HDM2 that demonstrates in suitable analysis and the interactional inhibition between the p53. These analyses comprise the method for estimating its performance, in the embodiment that follows more detailed description are arranged. Utilize these analyses, can determine whether compound has antiproliferative activity of the present invention.

Therefore preferred embodiment of the present invention relates to the purposes of one or more formulas I compound in the treatment proliferative disease. Preferably, described proliferative disease is cancer or leukaemia. Term used herein " proliferative disease " comprises any needs disease of control cell cycle in broad sense, for example angiocardiopathy such as ISR and heart disease, autoimmune disease such as glomerulonephritis and rheumatoid arthritis, skin disease such as psoriasis, anti-inflammatory, antimycotic, anti parasitic disease such as malaria, wind-puff and alopecia. In these diseases, compound of the present invention can be induced as required apoptosis or be kept stagnating in required cell.

Any step or the stage in compound cycle capable of inhibiting cell of the present invention, for example, the formation of nuclear membrane, from the deviating from of resting stage cell cycle (G0), G1 advances, the startup of chromosome decondensation, nuclear membrane destruction, START, dna replication dna, copy advance, the termination of dna replication dna, centerbody copy, G2 advances, activation, chromosome cohesion, centerbody separation, microtubule nucleation, the spindle of mitosis or meiosis function form and play a role, separate and separate with interaction, the chromatid of microtubule motor protein, formation and the cytokinesis effect of mitosis effect inactivation, contractile ring. Particularly, compound of the present invention may affect some gene functions such as chromatin in conjunction with, copy complex formation, copy allowance, composition that phosphorylation or other secondary modification activity, proteolysis, microtubule become nuclear activity and are bonded to the cell cycle signal transduction pathway in conjunction with, actin combination, every protein combination, microtubule organizing center.

In one embodiment of the invention, the compound of formula I or Ia gives with the amount that is enough to suppress at least a CDK enzyme.

In preferred embodiment of the present invention, the compound of formula I preferably gives with the amount that is enough to suppress to relate to the host cell CDKs of one or more virus replication, be CDK2, CDK7, CDK8 and CDK9[Wang D, De la Fuente C, Deng L, Wang L, Zilberman I, Eadie C, Healey M, Stein D, Denny T, Harrison LE, Meijer L, Kashanchi F.Inhibition of human immunodeficiency virus type I transcription by chemical cyclin-dependent kinase inhibitors.J.Virol.2001; 75:7266-7279].

Such as definition here, the antiviral effect in the scope of the invention can be confirmed by the activity that suppresses CDK2, CDK7, CDK8 or CDK9. The analysis that is used for definite CDK activity has been carried out more detailed description at the embodiment that follows. Utilize described enzyme analysis, can determine whether compound has the antiviral activity of the present invention's definition.

In particularly preferred embodiments, described formula Ia compound can be used for treating viral disease, such as human cytomegalovirus (HCMV), herpes simplex types 1 virus (HSV-1), I type human immunodeficiency virus (HIV-1) and varicella virus (VZV).

In particularly preferred embodiments, the present invention relates to the application of one or more formulas Ia compound in the viral disease for the treatment of CDK dependence or sensitiveness. CDK dependence disease is relevant above normal activity level with one or more CDK enzymes. This class disease is preferably relevant with the unusual activity level of CDK2, CDK7, CDK8 and/or CDK9. CDK sensitiveness disease is that CDK level not normal is not main cause but the elementary different not normal disease that causes of thanking in downstream. In this case, CDK2, CDK7, CDK8 and/or CDK9 are considered to the part of sensitiveness metabolic pathway, and therefore the CDK inhibitor can have activity in this class disease for the treatment of.

The preferred embodiment of the present invention relates to formula Ie compound or pharmaceutically acceptable salt thereof, for the preparation of the treatment viral disease medicine in purposes,

Wherein

X ¹And X²One of be S, X¹And X²In another be N;

(i)-single-, two-or polyhydroxylated alicyclic group;

-two-or polyhydroxylated aliphatic or aromatic group;

-carbohydrate derivative;

-halogenated alkyl carbonyl;

(ii)COOH，SO ₃H，OSO ₃H，PO ₃H ₂Or OPO₃H ₂；

-SO ₂-alkyl;

-alkyl, optional by one or more OH group replacement;

-CO-alkyl;

-aralkyl;

-COO-alkyl; And

-ether, optional by one or more OH group replacement; And

Wherein Y is not pyridine radicals;

(iv) natural or non-natural amino acid, peptide or peptide derivative;

R ¹¹For as above-mentioned for R⁹And R¹⁰(i) in the definition or solubilizing group (iv); Or be selected from:

(v)OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

(vi) Y as defined above, but be not guanidine and quaternary amine;

(vii)NHCO(CH ₂) _m[NHCO(CH ₂) _m’] _p[NHCO(CH ₂) _m”] _qY, wherein p and q respectively are 0 or 1, and m, m ' and m " respectively do for oneself to 10 integer; And

(viii)NHCOR ¹²Or NHSO₂R ¹³, R wherein¹²And R¹³Respectively doing for oneself optional comprises one or more heteroatomic alkyl, and described group is optional is selected from OH, NH by one or more₂, halogen and NO₂Substituting group replace;

(ix) ether or polyethers optional are replaced by one or more hydroxyl;

Preferred feature is with as above for the definition of formula I, Ia, Ib and Ic compound.

In preferred embodiments, the compound of formula I is selected from those listed in table 1 compounds.

More preferably, described formula Ia compound is selected from following compound: [1], [3], [4], [15] and [53].

For being used for the treatment of viral disease, preferably the compound of formula I can suppress CK2, CDK7 and/or CDK9 and be selected from following compound:

2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide;

2-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide;

[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine;

3-(1-{4-[4-(2,4-, two-methyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperidines-4-yl)-third-1-alcohol;

[4-(4-benzyl-piperazine-1-yl)-phenyl]-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-yl]-amine; And

3-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide.

Observe following compound and be effective especially antivirotic, as use the analysis based on cell to confirm: [4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine.

The present invention relates to formula I or Ia compound on the other hand as antimitotic agent.

The present invention relates to the purposes that formula I or Ia compound are used for the treatment of neural DD on the other hand.

Preferably, described neural DD is the neuron Apoptosis.

The present invention relates to formula I or Ia compound on the other hand as the purposes of antivirotic.

Therefore, the present invention relates to compound of the present invention on the other hand for the preparation of the treatment viral disease, such as the purposes in the medicine of human cytomegalovirus (HCMV), herpes simplex types 1 virus (HSV-1), I type human immunodeficiency virus (HIV-1) and varicella virus (VZV).

In preferred embodiment of the present invention, described compound of the present invention gives to be enough to suppressing one or more amount that relates to the host cell CDKs of virus replication, be CDK2, CDK7, CDK8 and CDK9[Wang D, De la Fuente C, Deng L, Wang L, Zilberman I, Eadie C, Healey M, Stein D, Denny T, Harrison LE, Meijer L, Kashanchi F.Inhibition of human immunodeficiency virus type I transcription by chemical cyclin-dependent kinase inhibitors.J.Virol.2O01; 75:7266-7279].

Such as definition here, the antiviral effect in the scope of the invention can be confirmed by the activity that suppresses CDK2, CDK7, CDK8 or CDK9.

In particularly preferred embodiments, the present invention relates to the application of one or more the compounds of this invention in the viral disease for the treatment of CDK dependence or sensitiveness. CDK dependence disease is relevant above normal activity level with one or more CDK enzymes. This class disease is preferably relevant with the unusual activity level of CDK2, CDK7, CDK8 and/or CDK9. CDK sensitiveness disease is that CDK level not normal is not main cause but the elementary different not normal disease that causes of thanking in downstream. In this case, CDK2, CDK7, CDK8 and/or CDK9 are considered to the part of sensitiveness metabolic pathway, and therefore the CDK inhibitor can have activity in this class disease for the treatment of.

The opposing party of the present invention aspect relates to formula I or Ia compound or pharmaceutically acceptable salt thereof for the preparation of the purposes in the medicine for the treatment of diabetes.

In particularly preferred embodiments, described diabetes are type ii diabetes.

GSK3 is a kind of in several protein kinases of phosphorylation glycogen synthetase (GS). The stimulus that the right glycogen of insulin synthesizes in the skeletal muscle is from dephosphorylation and the activation of GS. Therefore, GSK3 causes the latter's inactivation to the effect of GS and therefore suppresses in the muscle glucose to the conversion of glycogen.

Type ii diabetes (non--IDD) is a kind of multi-factor disease. Hyperglycemia is because the insulin resistance in liver, muscle and its hetero-organization and impaired insulin secretion cause. Skeletal muscle is the main position of the glucose uptake of insulin-stimulation, and it leaves circulation or changes into glycogen there. The muscle glycogen deposition is the active major decision link of glucose adjustment, and II type diabetes have the muscle glycogen storage of shortage. Evidence suggests very important [Chen, Y.H. in the active II type that the is increased in diabetes of GSK3; Hansen, L.; Chen, M.X.; Bjorbaek, C.; Vestergaard, H.; Hansen, T.; Cohen, P.T.; Pedersen, O.Diabetes, 1994,43,1234]. In addition, confirmed that GSK3 crosses expression and have inversely related [Nikoulina, S.E. between skeletal muscle GSK3 activity and insulin effect in the muscle cell of type ii diabetes; Ciaraldi, T.P.; Mudaliar, S.; Mohideen, P.; Carter, L.; Henry, R.R.Diabetes, 2000,49,263].

Therefore, the treatment diabetes that are suppressed at of GSK3 especially have the treatment meaning in type ii diabetes and the diabetic neuropathy.

The many substrates of known GSK3 phosphorylation except GS, therefore and participate in the adjusting of multiple biochemical path. For example, GSK high expressed in maincenter and peripheral neverous system.

Therefore the present invention relates to formula I or Ia compound or pharmaceutically acceptable salt thereof on the other hand, for the preparation of the treatment CNS disease purposes in the medicine of neural DD for example.

Preferably, described CNS disease is Alzheimer's.

Tau is for participating in the etiologic etiological GSK-3 substrate of Alzheimer's. In the nerve cell of health, Tau and tubulin are copolymerized into microtubule. But in Alzheimer's, tau has formed large thread entanglement, has destroyed the micro-tubular structure in the nerve cell, thereby damages the transmission of nutrition and the transmission of neural information.

Wish not limited to by theory, believe that the GSK3 inhibitor can prevent and/or reverse the unusual hyperphosphorylation of microtubule-GAP-associated protein GAP tau, the latter be Alzheimer's and many other neural DD such as the invariant features of stein-leventhal syndrome, the sex change of cortex matrix and Pick's disease. Sudden change in the tau gene causes the mode of inheritance of frontotemporal dementia, further supports the relation [Goedert, M.Curr.Opin.Gen.Dev., 2001,11,343] between Protein tau dysfunction and the neurodegeneration.

The present invention relates to formula I or Ia compound or pharmaceutically acceptable salt thereof on the other hand, for the preparation of the treatment bipolar disorder (bipolar disorder) medicine in purposes.

On the other hand, the present invention relates to formula I or Ia compound or pharmaceutically acceptable salt thereof, for the preparation of the treatment apoplexy medicine in purposes.

Reduction neuron Apoptosis is the important therapeutic purpose [Mattson, M.P.Nat.Rev.Mol.Cell.Biol., 2000,1,120] in head trauma, apoplexy, epilepsy and the motor neuron disease. Therefore, as the short apoptosis factor in the neuron cell, GSK3 becomes this protein kinase and is designed for attractive treatment target in the suppressive drug for the treatment of these diseases.

The present invention relates to formula I or Ia compound or pharmaceutically acceptable salt thereof on the other hand, for the preparation of the treatment alopecia (alopecia) medicine in purposes.

Hair growth is subjected to the especially control of Wnt-3 signal path of Wnt signal path. Organizing in the culture model system of skin, the expression of the nondegradable mutant of beta-catenin causes the remarkable increase of the quantity of the stem cell of inferring, and it has larger propagation active [Zhu, A.J.; Watt, F.M.Development, 1999,126,2285]. This population of stem cells body surface reach high-caliber non--cadherin-relevant beta-catenin [DasGupta, R.; Fuchs, E.Development, 1999,126,4557], it can promote high propagation active. In addition, brand-new sending out-scrotiform attitude generation occurs in the transgenic mice of the beta-catenin of overexpression brachymemma in the skin, only forms middle just generation the embryo under normal circumstances. Therefore the unusual use of GSK3 inhibitor can be used for treating baldness and can be used for the recovery of the natural on-off cycles of hair growth of the alopecia that chemotherapy induces.

The present invention relates to the method for the treatment of GSK3-dependence disease on the other hand, and described method comprises uses as above definition I compound or Ia or its officinal salt to the object of needs with the amount that is enough to suppress GSK3.

Preferably, described compound or pharmaceutically acceptable salt thereof of the present invention gives with the amount that is enough to suppress GSK3 β.

In a kind of embodiment of the present invention, described the compounds of this invention gives with the amount that is enough to suppress at least a PLK enzyme.

Polo sample kinases (PLKs) is by serine/Serineprotein kinase man group composition. Demonstrate spindle unusual [Sunkel etc., J.Cell Sci., 1988,89,25] and find polo coding mitotic kinase [Llamazares etc., Genes Dev., 1991,5,2153] in the mitosis fruit bat melanogaster in polo site sudden change. In human body, there is the PLKs[Glover of three kinds of height correlations etc., Genes Dev., 1998,12,3777]. Its amino-end catalytic kinase domain and its c-terminus that comprises the height homology comprises two or three conservative regions, the polo box. Not exclusively understand at present the function of polo box, but it participates in PLKs target subcellular fraction district [Lee etc., Proc.Natl.Acad.Sci.USA, 1998,95,9301; Leung etc., Nat.Struct.Biol., 2002,9,719], regulate and the interaction [Kauselmann etc. of other albumen, EMBO J., 1999,18,5528] or consisted of self-regulation domain part [Nigg, Curr.Opin.Cell Biol., 1998,10,776]. In addition, polo box-dependence PLK1 activity is necessary [Yuan etc., Cancer Res., 2002,62,4186 to correct mid-term/later stage conversion and cytokinesis; Seong etc., J.Biol.Chem., 2002,277,32282].

Studies show that the more mitotic basic sides of people PLKs adjusting [Lane etc., J.Cell.Biol., 1996,135,1701; Cogswell etc., Cell Growth Differ., 2000,11,615]. Particularly, it is believed that the PLK1 activity to G2 later stage/early stage early interim centerbody functional maturation and the formation of bipolar spindle subsequently be essential. Consuming interior verified this albumen of PLK1 of cell by little RNA interfering (siRNA) technology is essential [Liu etc., Proc.Natl.Acad.Sci.USA, 2002,99,8672] to finishing of multiple mitosis process and cytokinesis.

In preferred embodiment of the present invention, described compound of the present invention gives with the amount that is enough to suppress PLK1.

In three-type-person PLK, PLK1 characterizes the most abundant; Its adjusting various kinds of cell is split a minute cycle activity and is comprised mitotic initial [Toyoshima-Morimoto etc., Nature, 2001,410,215; Roshak etc., Cell.Signalling, 2000,12,405], the DNA-infringement outpost of the tax office activates [Smits etc., Nat.Cell Biol., 2000,2,672; Van Vugt etc., J.Biol.Chem., 2001,276,41656], regulate anaphase-promoting complex [Sumara etc., Mol.Cell, 2002,9,515; Golan etc., J.Biol.Chem., 2002,277,15552; Kotani etc., Mol.Cell, 1998,1,371], the phosphorylation [Feng etc., Cell Growth Differ., 2001,12,29] of proteasome and copying and ripe [Dai etc., Oncogene, 2002,21,6195] of centerbody.

Particularly, mitotic startup requires activation M-m phage promoting factor,MPF M (MPF), the compound [Nurse, Nature, 1990,344,503] between cyclin dependence kinase c DK1 and the B-type cyclin. The latter assembled and promotes WEE1, MIK1 and MYT1 kinases to the inhibitory action of the phosphorylation of MPF compound in the S of cell cycle and G2 phase. In the G2 phase in the end of term, the corresponding dephosphorylation that is caused by dual-specificity phosphatase CDC25C causes the activation [Nigg, Nat.Rev.Mol. Cell Biol., 2001,2,21] of MPF. In the interkinesis, cyclin B is positioned to cytoplasm [Hagting etc., EMBO J., 1998,17,4127], then early stage phosphorylation and this event cause nuclear transposition [Hagting etc., Curr.Biol., 1999,9,680; Yang etc., J.Biol.Chem., 2001,276,3604]. Assemble at the nuclear of the MPF of the activity in early stage and to be considered to starting M-phase event very important [Takizawa etc., Curr.Opin.Cell Biol., 2000,12,658]. But because WEE1, nuclear MPF keeps non-activity, unless neutralized by CDC25C. Phosphatase CDC25C is positioned to cytoplasm in the interkinesis certainly, and assembles [Seki etc., Mol.Biol.Cell, 1992,3,1373 in early stage in nuclear; Heald etc., Cell, 1993,74,463; Dalal etc., Mol.Cell.Biol., 1999,19,4465]. Cyclin B[Toyoshima-Morimoto etc., Nature, 2001,410,215] and CDC25C [Toyoshima-Morimoto etc., EMBO Rep., 2002,3,341] nuclear of the two enters and can be promoted [Roshak etc., Cell.Signalling, 2000 by the phosphorylation of PLK1,12,405]. This kinases is the important regulatory factor that starts the M-phase.

In a kind of particularly preferred embodiment, compound of the present invention is ATP-Antagonism PLK1 inhibitor.

In the present invention, the ATP Antagonism refers to that the inhibitor compound reduces or prevents the PLK catalytic activity, namely is transferred to the activity of large molecule PLK substrate from ATP phosphoric acid, with a kind of mode that weakens or destroy ATP combination desmoenzyme avtive spot reversibly or irreversibly.

In another preferred embodiment, described the compounds of this invention gives with the amount that is enough to suppress PLK2 and/or PLK3.

Mammal PLK2 (known also is SNK) and PLK3 (known also is PRK and FNK) are shown as direct early gene product at first. As if the PLK3 kinase activity peak in S later stage and G2 phase. It also activates during the activation of the DNA infringement outpost of the tax office and serious oxidative stress. PLK3 also plays a significant role in the adjusting of microtubule dynamics and centerbody function in cell, and PLK3 expression downward modulation causes cell cycle arrest and Apoptosis [Wang etc., Mol.Cell.Biol., 2002,22,3450]. PLK2 is that understanding is minimum among three kinds of PLKs. The two may also have function [Kauselmann etc., EMBO J., 1999,18,5528] after other the important mitosis PLK2 and PLK3.

The present invention relates on the other hand formula I compound and is used for the kinase whose purposes of CKIs.

In preferred embodiment aspect this, protein kinase is cyclin dependence kinases. Preferably, described protein kinase is CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 or CDK9, more preferably CDK2.

Another aspect of the present invention relates to the kinase whose method of CKIs, and described method comprises described protein kinase is contacted with formula I compound.

In preferred embodiment aspect this, protein kinase is cyclin dependence kinases, even CDK2 more preferably.

Pharmaceutical composition

Other aspects of the present invention relate to a kind of pharmaceutical composition, comprise that the formula I compound such as the first aspect definition mixes with one or more pharmaceutically acceptable diluents, excipient or carrier. Although even compound of the present invention (comprising its officinal salt, ester and acceptable solvent compound) can be individually dosed, they are with pharmaceutically suitable carrier, excipient or diluent administration, when treating in particular for the people usually. The human or animal that pharmaceutical composition can be used among people and the animal doctor uses.

Here the example of various multi-form suitable excipient of the pharmaceutical composition of record is found in " Handbook of Pharmaceutical Excipients, 2^ndEdition, (1994) are write by A Wade and PJ Weller.

Acceptable carrier or the diluent for the treatment of purposes are known in the pharmacy field, and, for example, Remington ' s Pharmaceutical Sciences puts down in writing among the Mack Publishing Co. (A.R.Gennaro edit. 1985).

The example of suitable carrier comprises lactose, starch, glucose, methylcellulose, dolomol, sweet mellow wine, sorbierite etc. The example of suitable diluent comprises ethanol, G ﹠ W.

Medicinal carrier, excipient or diluent can be selected according to the pharmacy standard of the method for administration that will use and standard. Pharmaceutical composition can comprise conduct or any suitable adhesive, lubricant, suspending agent, coating agent, cosolvent except carrier, excipient or diluent.

The example of suitable adhesive comprises starch, gelatin, natural carbohydrate such as glucose, Lactis Anhydrous, free-pouring lactose, beta lactose, corn sweetener, natural and synthetic rubber, such as gum arabic, gum tragacanth or mosanom, carboxy methyl cellulose and polyethylene glycol.

The example of proper lubrication agent comprises enuatrol, odium stearate, dolomol, Sodium Benzoate, sodium acetate, sodium chloride etc.

Anticorrisive agent, stabilizing agent, dyestuff and even flavor enhancement can in pharmaceutical composition, provide. The example of anticorrisive agent comprises the ester class of Sodium Benzoate, sorbic acid and p-hydroxybenzoic acid. Also can use antioxidant and suspending agent.

Salt/ester

Formula I or Ia compound can salt or ester especially the form of the acceptable salt of medicine or ester provide.

The drug acceptable salt of the compounds of this invention comprises sour addition salts or the base addition salts that they are suitable. The people's such as the visible Berge of summary of suitable drug salt J.Pharm Sci, 66,1-19 (1977). The salt that salt is and for example following acid forms: strong inorganic acid, such as mineral acid, for example sulfuric acid, phosphoric acid or halogen acids; Strong organic carboxylic acid is not as replacing or replace the alkane carboxylic acid of 1 to 4 carbon atom of (as by halo), for example acetic acid; Saturated or undersaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or neighbours' phthalic acid (tetraphthalic); Hydroxycarboxylic acid, for example ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; Amino acid, for example aspartic acid or glutamic acid; Benzoic acid; Or and organic sulfonic acid, as not replacing or replace (the C of (as by halo)₁-C ₄) alkyl sulfonic acid or aryl sulfonic acid, such as methanesulfonic acid or p-methyl benzenesulfonic acid.

Depend on esterified functional group, use organic acid or alcohol/hydroxide to form ester. Organic acid comprises carboxylic acid, as not replacing or replace the alkane carboxylic acid of 1 to 12 carbon atom of (as by halo), for example acetic acid; Saturated or undersaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or neighbours' phthalic acid; Hydroxycarboxylic acid, for example ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; Amino acid, for example aspartic acid or glutamic acid; Benzoic acid; Or and organic sulfonic acid, as not replacing or replace (the C of (as by halo)₁-C ₄) alkyl sulfonic acid or aryl sulfonic acid, such as methanesulfonic acid or p-methyl benzenesulfonic acid. Suitable hydroxide comprises the inorganic hydrogen oxide, such as NaOH, potassium hydroxide, calcium hydroxide, aluminium hydroxide. Alcohol comprises the alkanol that does not replace or replace 1 to 12 carbon atom of (as by halo).

Enantiomter/dynamic isomer

In aforementioned discussion of the present invention was aspect all, the present invention also suitably comprised whole enantiomters and the dynamic isomer of formula I or Ia compound. Those skilled in the art can recognize the compound of have optical property (one or more asymmetric carbon atom) or tautomerism feature. Can separate/prepare corresponding enantiomter and/or dynamic isomer by method as known in the art.

Stereoisomer and geometric isomer

Compounds more of the present invention can stereoisomer and/or the form of geometric isomer exist, for example they can have one or more asymmetric and/or geometric centers, and therefore can two kinds or multiple alloisomerism and/or geometric format exist. The present invention includes the use of all independent stereoisomers of these inhibitor medicaments and geometric isomer and their mixture. The term that uses in the claim comprises these forms, as long as described form keeps suitable functional activity (but needn't arrive identical degree).

The present invention also comprises all suitable isotope variants of medicament or its drug acceptable salt. The isotope variant of medicament of the present invention or its drug acceptable salt is defined as that at least one atom is wherein had identical atomic number but material that the different atom of atomic mass that atomic mass and occurring in nature are found usually replaces. The isotopic example that can be incorporated into medicament and its drug acceptable salt comprises the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, respectively as²H、 ³H、 ¹³C、 ¹⁴C、 ¹⁵N、 ¹⁷O、 ¹⁸O、 ³¹P、 ³²P、 ³⁵S、 ¹⁸F and³⁶Cl. Some isotope variants of medicament and its drug acceptable salt, for example the binding radioactivity isotope as³H or¹⁴Those compounds of C are useful in medicine and/or substrate tissue distribution research. What contain tritium is³H and carbon-14 are namely¹⁴The C isotope because of its easy preparation and detectability particularly preferably. In addition, with isotope such as deuterium be²The replacement of H can provide because of larger metabolic stability specific treatment benefit, and for example the half-life increases or dosage requires to reduce in the body, and therefore can be in some cases by preferably. The suitable isotope variant that usually can use suitable agent prepares the isotope variant of medicament of the present invention and its drug acceptable salt by conventional process.

Solvate

The present invention also comprises the purposes of the solvate form of the compounds of this invention. The term that uses in the claim comprises these forms.

Polymorph

The invention still further relates to the compound of the present invention of various crystal forms, polymorphic forms and anhydrous/hydrated form. As everyone knows, purification process that can be by changing a little used solvent in the preparation of this compou nd synthesis in medicine industry with or unpack format separate any this class form that obtains compound.

Pro-drug

The present invention also comprises the compound of the present invention of pro-drug form. This pro-drug is generally that one or more suitable groups have been modified so that the formula I compound that described modification can be reversed after to people or mammalian object administration. Although can with this pro-drug administration the second medicament, usually realize this reverse by naturally occurring enzyme in this class object in order to realize reversing in the body. The example that this class is modified comprises ester (for example above-mentioned in those any), wherein can reverse by esterase etc. Other this class system is known by those skilled in the art.

Administration

Can make pharmaceutical composition of the present invention be suitable in oral, rectum, vagina, parenteral, intramuscular, the peritonaeum, in the artery, in the sheath, interior, subcutaneous, the intracutaneous of bronchus, intravenous, nose, oral cavity or sublingual administration approach.

For oral administration, utilize especially compressed tablets, pill, tablet, gel (gellules), drops and capsule. Preferably, every dose of these composition comprise 1-250mg and the more preferably active ingredient of 10-100mg.

Other form of medication comprises solution or emulsion, and they can be in intravenous, artery, in the sheath, in subcutaneous, the intracutaneous, peritonaeum or intramuscular administration, but and by aseptic or sterile solution preparation. Pharmaceutical composition of the present invention also can be the form of suppository, pessary, supensoid agent, emulsion, washing lotion, ointment, cream, gel, spray, solution or face powder (dusting powder).

The alternative mode of percutaneous dosing is to utilize dermal patch. For example, active ingredient can be incorporated in the cream that is formed by polyethylene glycol aqueous emulsion or atoleine. Concentration that can also 1-10wt% is incorporated into active ingredient in the ointment that jointly is comprised of Chinese wax or white soft paraffin matrix and needed stabilizing agent and anticorrisive agent.

Every dose of active ingredient that can comprise 10-1000mg, preferred 10-250mg of injectable forms.

Composition can be formulated into unit dosage form, namely comprises the discrete portions of the form of the multiple unit of dosage unit or dosage unit or subunit.

In a kind of particularly preferred embodiment, intravenous administration associating of the present invention or pharmaceutical composition.

Dosage

Those of ordinary skill in the art need not additionally test the optimal dose that just can easily determine the composition of the present invention of patient's administration. Typically, the doctor can determine the optimal actual dose of individual patient, and adjust according to various factors, comprise the activity of the particular compound of use, metabolic stability and effect length, age, body weight, general health situation, sex, diet, administering mode and time, drainage rate, medicine associating, the order of severity of specific illness and the treatment that individuality is just being accepted of compound. Dosage disclosed herein is the example of ordinary circumstance. Certainly also can be useful higher or than the individual cases of low dosage scope, this all within the scope of the invention.

As required, can the 0.01-30mg/kg body weight, such as the 0.1-10mg/kg body weight, the more preferably described medicament of the dosed administration of 0.1-1 mg/kg body weight.

In exemplary embodiment, patient is used one or be used for the treatment of malignant tumour in multi-agent 10～150mg/ days.

Combination

In particularly preferred embodiments, other carcinostatic agents combination medicine-feeding of one or more compound of the present invention and one or more, for example, the existing anticancer medicine that provides on the market. In this case, compound of the present invention serially, side by side or in succession with one or more carcinostatic agents combination medicine-feeding.

The anticancer medicine is usually more effective when being used in combination. In particular, the combination therapy can be avoided the overlapping of main toxic action, mechanism of action and resistance mechanism. In addition, also can with maximum tolerated dose and between these dosage the time interval with minimum use most drug. The main advantage of medicine combination be possible by biochemistry interact promote to add and or possible synergy, and also may be reduced in chemical sproof appearance in the infantile tumour cell, the latter is in response to the initial chemotherapy of carrying out with single medicine. Utilize biochemical interactional example to be confirmed by the following fact when selecting drug regimen: using folinic acid increases the competent cell intracellular metabolite thing of 5 FU 5 fluorouracil to the combination of its target thymidylate synthase, thereby it is active to increase its cytotoxicity.

Many combinations have been used for cancer and leukemic treatment at present. The widely comment of medical practice visible " Oncologic Therapies " is write by E.E.Vokes and H.M.Golomb, is published by Springer.

Can by the research test-compound with known think in the concrete cancer of initial treatment or in derived from the clone of cancer the inhibition activity of valuable compound hint favourable combination. This method also can be used for measuring the order of using medicament, that is, and before, simultaneously or afterwards. Described dosage regimen can be the feature of all cell cycle effect medicines of identifying here.

Natural/non-natural amino acid

In a kind of preferred embodiment of the present invention, R⁹、R ¹⁰Or R¹¹Can be natural or non-natural amino acid.

Term used herein " non-natural amino acid " refers to Amino acid derivatives, and can for example comprise the methyl-derivatives of α and α-dibasic amino acid, N-alkyl amino acid, lactic acid, natural amino acid halo derivative such as trifluoro tyrosine, p-Cl-phenylalanine, p-Br-phenylalanine, p-I-phenylalanine, L-pi-allyl-glycine, Beta-alanine, L-butyrine L-GABA, L-α-aminoacid, L-ε-aminocaproic acid, 7-aminoheptylic acid, METHIONINE sulfone, L-nor-leucine, L-norvaline, p-nitro-L-phenylalanine, L-hydroxy-proline, L-Thioproline, phenylalanine (Phe) such as 4-methyl-Phe, pentamethyl-Phe, L-Phe (4-is amino), L-Tyr (methyl), L-Phe (4-isopropyl), L-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), L-diaminopropionic acid and L-Phe (4-benzyl).

Device

In a kind of preferred embodiment of the present invention, R⁹、R ¹⁰Or R¹¹Group is allowed 2-phenyl amino-4-heteroaryl-pyrimidine compound is fixed on the carrier. For example, R⁹、R ¹⁰Or R¹¹Group can comprise the chemical functional group, be used for covalently bound to solid phase, on the polymer (such as agarose, polyacrylamide, polystyrene etc.) such as the functionalization that usually sees matrix (hole of microtiter plate, microballon, film etc.), or be used for biochemical analysis or affinity chromatography. Perhaps, R⁹、R ¹⁰Or R¹¹Group can be connected to other little molecule (such as biotin) or polypeptide (such as antigen), it can be used for non-covalent fixing, by be bonded to fixing acceptor (as under the situation of biotin for Avidin or streptavidin, or be specific antibody under the situation of antigen).

Analyze

The present invention relate on the other hand as previously defined formula I or the Ia compound in the purposes of the analysis of candidate compound that be used for to differentiate other, described candidate compound affects the activity of one or more CDK enzyme.

Preferably, described analysis can be differentiated the candidate compound that can suppress one or more CDK enzyme, GSK or PLK enzyme.

More preferably, described analysis is competitive binding analysis.

Preferably, candidate compound produces by compound of the present invention being carried out conventional SAR modification.

Term used herein " conventional SAR modifies " refers to the standard method by the given compound of chemically derived change as known in the art.

Therefore, on the one hand, the compound of discriminating can be used as model (for example, template), is used for developing other compound. The compound that uses in these tests can be free state in the solution, is fixed on the solid support, is bonded to cell surface or is positioned at cell. Can measure the disappearance in conjunction with complex formation or activity between the reagent of described compound and test.

Analysis of the present invention can be a kind of screening, wherein tests a large amount of reagent. On the one hand, analytical method of the present invention is high flux screening.

The present invention also comprises and utilizes the competitive drug screening assay analysis, neutralizing antibody that wherein can binding compounds specifically with test-compound competition binding compounds.

The another kind of technology that is used for screening is the high flux screening (HTS) that material is had the reagent of suitable binding affinity, and based on the method for in WO 84/03564, describing in detail.

Expect that analytical method of the present invention is suitable for the screening of little and large-scale test-compound and is used for quantitative analysis.

Preferably, the known substrate existence that competitive binding assay is included in described CDK enzyme contacts formula I or Ia compound down with the CDK enzyme, and detects the interactional any variation between described CDK enzyme and the described known substrate.

The present invention provides on the other hand a kind of and has been bonded to the method for CDK enzyme, described comprising the steps: for detection of part

(i) in the presence of the known substrate of described CDK enzyme, part is contacted with the CDK enzyme;

(ii) the interactional any variation between the described CDK enzyme of detection and the described known substrate;

And wherein said part is formula I or Ia compound.

One aspect of the present invention relates to a kind of method, comprises the steps:

(a) carry out above-mentioned analytical method;

(b) differentiate that one or more can be bonded to the part of part binding structural domain; And

(c) a certain amount of described one or more part of preparation.

The present invention provides a kind of method on the other hand, comprises the steps:

(a) carry out above-mentioned analytical method;

(c) preparation comprises the pharmaceutical composition of described one or more part.

The present invention relates to a kind of method on the other hand, comprises the steps:

(a) carry out above-mentioned analytical method;

(c) modify one or more described part that can be bonded to the part binding structural domain;

(d) carry out above-mentioned analytical method;

(e) the standby pharmaceutical composition that comprises described one or more part of optional system.

The invention still further relates to the part that utilizes above-mentioned method to identify.

The present invention also relates to the pharmaceutical composition that comprises the part that utilizes above-mentioned method evaluation on the other hand.

The present invention relates on the other hand and utilizes part that above-mentioned method identifies for the preparation of the purposes in the pharmaceutical composition for the treatment of proliferative disease.

Above-mentioned method can be used for screening the part of the inhibitor that can be used as one or more CDK enzyme.

The present invention further describes by way of example.

Embodiment

Embodiment 1

Chemical synthesis

The covalently bound of solubilising composition realizes (Wermuth CG.Preparation of water-soluble compounds by covalent attachment of solubilizing moieties.In:Practice of Medicinal Chemistry by many different modes well known in the art; Academic Press:London, UK, 1996; Pp 755-776). For example, the amino substituting group in 2-phenyl amino-4-heteroaryl-pyrimidine derivative or its synthetic precursor can carry out acyl group or alkylation with the carbonyl functional group in the suitable solubilising composition precursor. Similarly, the carbonyl in 2-phenyl amino-4-heteroaryl-pyrimidine derivative can carry out ammonification or alkylation with suitable solubilising composition precursor. Halogen group on the fragrant C in phenyl amino-4-heteroaryl-pyrimidine or the precursor can replace with the nucleophilic group in the solubilising composition precursor. Suitable 2-phenyl amino-4-heteroaryl-pyrimidine precursor can be prepared (Fischer PM, Wang S.PCT Intl.Patent Appl.Publ.WO 01/072745 according to the instruction of Fischer etc.; Cyclacel Limited, UK, 2001). Some synthetic and analyze details for example the compounds of this invention (referring to table 1) provide among the embodiment 2 below.

Embodiment 2

[4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine [1].

By N '-[5-(3-dimethylamino-acryloyl group)-4-methyl-thiazole-2-yl]-N; N-dimethyl-carbonamidine (prepares from the condensation reaction between 1-(2-amino-4-methyl-thiazole-5-yl)-ethyl ketone and DMF dimethylacetal prepare) and N-(4-morpholine-4-base-phenyl)-guanidine nitrate.

Yellow solid. M.p.300-304 ℃.

¹H-NMR(DMSO-d ₆)δ：2.46(s，3H，CH ₃)，3.07(m，4H，CH ₂)，3.76(m，4H， CH ₂), 6.85 (d, 1H, J=5.3Hz, pyrimidine radicals-H), 6.92 (m, 2H, Ph-H), 7.53 (br.s, 1H, NH), 7.67 (m, 2H, Ph-H), 8.30 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 9.25 (br.s, 1H, NH).

MS(ESI ⁺)m/z 369[M+H] ⁺(C ₁₈H ₂₀N ₆OS theoretical value 368.5).

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine [2].

Utilize the condensation reaction between 3-dimethylamino-1-(2,4-dimethyl-thiazole-5-yl)-propenone and N-(4-morpholine-4-base-phenyl)-guanidine nitrate to prepare. Linen solid.

¹H-NMR(CDCl ₃)δ：2.69(s，3H，CH ₃)，2.70(s，3H，CH ₃)，3.14(t，4H，J＝4.8 Hz，CH ₂)，3.72(t，4H，J＝4.9Hz，CH ₂), 6.89 (d, 1H, J=5.1Hz, pyrimidine radicals-H), and 6.95 (d, 2H, J=8.8Hz, Ph-H), 6.98 (br.s, 1H, NH), 7.53 (d, 2H, J=9.1Hz, Ph-H), 8.38 (d, 1H, J=5.1Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 368[M+H] ⁺(C ₁₉H ₂₁N ₅OS theoretical value 367.5).

[4-(2-N-methylamino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholino phenyl)-amine [3]

Utilize the condensation reaction between 3-dimethylamino-1-(4-methyl-2-methylamino thiazole-5-yl)-propenone (preparing from 1-(4-methyl-2-methylamino-thiazole-5-yl)-ethyl ketone and DMF dimethylacetal) and N-(4-morpholine-4-base-phenyl)-guanidine nitrate to prepare. Linen solid.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=10.8 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞95%).

¹H-NMR(DMSO-d ₆)δ：2.83(s，3H，CH ₃)，2.84(s，3H，CH ₃)，3.01(t，4H，J＝ 5.0Hz，CH ₂)，3.72(t，4H，J＝5.0Hz，CH ₂), 6.81 (d, 2H, J=5.5Hz, pyrimidine radicals-H), 6.87 (m, 2H, Ph-H), 7.61 (m, 2H, Ph-H), 8.12 (br.s, 1H, NH), 8.26 (d, 1H, J=5.5 Hz, pyrimidine radicals-H), 9.19 (br.s, 1H, NH).

MS(ESI ⁺)m/z 383[M+H] ⁺(C ₁₉H ₂₂N ₆OS theoretical value 382.5).

[4-(2-ethyl amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine [4].

(2-ethyl amino-4-methyl-thiazole-5-yl)-propenone (prepares from the condensation reaction between 1-(2-ethyl amino-4-methyl-thiazole-5-yl)-ethyl ketone and DMF dimethylacetal prepare) and N-(4-morpholine-4-base-phenyl)-guanidine nitrate to utilize 3-dimethylamino-1-. Linen solid.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=19.4 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞95%).

¹H-NMR(DMSO-d ₆)δ：1.16(t，J＝7.5Hz，3H，CH ₃)，2.48(s，3H，CH ₃)， 3.26(m，2H，CH ₂)，3.01(t，4H，J＝5.0Hz，CH ₂)，3.72(t，4H，J＝5.0Hz，CH ₂), 6.80 (d, 2H, J=5.5Hz, pyrimidine radicals-H), 6.86 (d, 2H, J=9.0Hz, Ph-H), 7.60 (d, 2H, J=9.0Hz, Ph-H), 8.25 (d, 1H, J=5.0Hz, pyrimidine radicals-H), 8.50 (s, 1H, NH), 9.16 (br.s, 1H, NH).

1-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-ethyl ketone [5]

With 1-fluoro-4-nitrobenzene (6.7g, 47.5mmol), 1-piperazine-1-base-ethyl ketone (6.7g, 52.3mmol) and K₂CO ₃(6.6g, 47.5mmol) solution in DMSO (60mL) was 100 ℃ of heating 18 hours. After the cooling, mixture is poured into H₂Among the O (0.5L). Filter the yellow mercury oxide that forms and use H₂The O washing obtains 1-[4-(4-nitro-phenyl)-piperazine-1-yl]-ethyl ketone (11.9g). It is partly dissolved among EtOH (100 mL) and the AcOH (50mL). Mixture is warmed to about 65 ℃ and add iron powder (325 orders, 12.0g, 215mmol) with the amount of each 1-g. Mixture is added hot reflux 2 hours and filters the Celite pad. Evaporated filtrate obtains the dark oil thing, and the adding 2M NaOH aqueous solution is regulated alkalescence and extracted with EtOAc. With the organic matter salt water washing that merges, at MgSO₄Upper drying is filtered and vacuum evaporation obtains the 1-[4-(4-amino-phenyl) of yellow solid-piperazine-1-yl]-ethyl ketone (6.7g). Partly this material (2.0g, 9.12 mmol) is dissolved among the EtOH (5mL) and adds HNO₃(69% aqueous solution, 1.26mL, 19.61 mmol) then add cyanamide (the 50%w/v aqueous solution, 2.48mL, 31.92mmol). The mixture that forms was added hot reflux 18 hours. Be cooled to room temperature and be poured into Et₂Among the O (100mL). Tell ether layer and concentrated. Filter the precipitation that forms and use iPrOH/Et₂Then the O washing uses pure Et₂The O washing. Beige solid drying is obtained N-[4-(4-acetyl group-piperazine-1-yl)-phenyl]-guanidine nitrate (1.2g). Be dissolved in this material (1.1g, 2.84mmol) in the 2-methyl cellosolve (14mL) and add K₂CO ₃(0.79g, 5.68mmol) then adds 3-dimethylamino-1-(2,4-dimethyl-thiazole-5-yl)-propenone (0.60g, 2.84mmol). The mixture that obtains was heated 18 hours at 115 ℃. Cooling is also concentrated. With residue through SiO₂Chromatogram (9:1 EtOAc/2M NH₃MeOH solution) purifying and from iPr₂Recrystallization obtains the title compound (930mg) of light brown solid among the O/MeOH.

¹H-NMR(CDCl ₃)δ：2.15(s，3H，CH ₃)，2.69(s，3H，CH ₃)，2.71(s，3H，CH ₃)， 3.12(t，2H，J＝5.4Hz，CH ₂)，3.15(t，2H，J＝5.4Hz，CH ₂)，3.63(t，2H，J＝5.4Hz， CH ₂)，3.79(t，2H，J＝5.4Hz，CH ₂), 6.90 (d, 1H, J=5.4Hz, pyrimidine radicals-H), and 6.96 (m, 2H, Ph-H), 6.98 (br.s, 1H, NH), 7.54 (m, 2H, Ph-H), 8.39 (d, 1H, J=5.4Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 409.6(C ₂₁H ₂₄N ₆OS theoretical value 408.5).

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-piperazine-1-base-phenyl)-amine [6].

(4-{4-[4-(2 to 1-, 4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-ethyl ketone (0.67g, 1.64mmol) adds 2M aq HCl (25mL) with stable speed in the solution of EtOH (3mL). Mixture was added hot reflux 1 hour, and cooling also adds solid Na₂CO ₃Regulate alkalescence. Product is extracted with EtOAc. With the organic matter salt water washing that merges, at Na₂SO ₄Upper drying, filtration and evaporation obtain the title compound (580mg) of yellow solid.

¹H-NMR(CDCl ₃)δ：2.62(s，3H，CH ₃)，2.63(s，3H，CH ₃)，2.99(m，4H，CH ₂)， 3.06(m，4H，CH ₂), 6.81 (d, 1H, J=5.4Hz, pyrimidine radicals-H), and 6.89 (m, 3H, Ph-H, NH), 7.44 (m, 2H, Ph-H), 8.31 (d, 1H, J=5.4Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 367(C ₁₉H ₂₂N ₆S theoretical value 366.5).

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[4-(4 '-2 "-the ethoxy ethanol piperazinyl)-phenyl]-amine [7]

With [4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-piperazine-1-base-phenyl)-amine (0.1g, 0.27mmol), 2-(2-chloro-ethyoxyl)-ethanol (35 μ L, 0.33mmol), NaI (49mg, 0.33mmol) and K₂CO ₃(37mg, 0.27mmol) mixture in MeCN (2mL) utilizes microwave reactor (SmithCreator, Personal Chemistry Ltd) 170 ℃ of heating 15 minutes in sealed tube. The evaporation solvent to dry doubling with residue through SiO₂Chromatogram (98:2 to 95:5EtOAc/2M NH₃MeOH solution) purifying obtains the title compound (78mg) of yellow foam.

¹H-NMR(CDCl ₃)δ：2.69(s，3H，CH ₃)，2.71(s，3H，CH ₃)，2.80-2.91(m，6H， CH ₂)，3.30(m，4H，CH ₂)，3.67(m，2H，CH ₂)，3.73(m，2H，CH ₂)，3.79(m，2H，CH ₂), 6.89 (d, 1H, J=5.4Hz, pyrimidine radicals-H), and 6.97 (m, 3H, Ph-H ﹠ NH), 7.52 (m, 2H, Ph-H), 8.02 (br.s, 1H, OH), 8.38 (d, 1H, J=5.4Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 456(C ₂₃H ₃₀N ₆O ₂S theoretical value 454.6).

3-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-third-1-alcohol [8]

Yellow solid.

¹H-NMR(CDCl ₃)δ：2.69(s，3H，CH ₃)，2.71(s，3H，CH ₃)，2.75(m，2H，CH ₂)， 3.21(m，2H，CH ₂)，3.84(t，2H，J＝5.1Hz，CH ₂), 6.89 (d, 1H, J=5.4Hz, pyrimidine radicals-H), and 6.95 (m, 2H, Ph-H), 6.98 (br.s, 1H, NH), 7.51 (m, 2H, Ph-H), 8.38 (d, 1H, J=5.4Hz, pyrimidine-H).

MS(ESI ⁺)：m/z 425.8(C ₂₂H ₂₈N ₆OS theoretical value 424.6).

2-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-ethanol [9]

Yellow solid.

¹H-NMR(CDCl ₃)δ：2.55(t，2H，J＝5.4Hz，CH ₂)，2.62(m，10H，CH ₃ & CH ₂)， 3.12(t，4H，J＝4.9Hz，CH ₂)，3.60(t，2H，J＝5.4Hz，CH ₂), 6.81 (d, 1H, J=5.4Hz, pyrimidine radicals-H), and 6.88 (m, 2H, Ph-H), 7.05 (b r.s, 1H, NH), 7.45 (m, 2H, Ph-H), 8.30 (d, 1H, J=5.1Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 411.7(C ₂₁H ₂₆N ₆OS theoretical value 410.5).

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[4-(4-mesyl-piperazine-1-yl)-phenyl]-amine [10]

To [4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-piperazine-1-base-phenyl)-amine (86mg, 0.23mmol) at anhydrous CH₂Cl ₂Add Et in the solution (2mL)₃N (39 μ L, 0.28mmol). After being cooled to 0 ℃, drip mesyl chloride (22 μ L, 0.28mmol). Stir after 15 minutes, reactant mixture is warmed to room temperature and continues stirred 18 hours. After the evaporation, with residue through SiO₂Chromatogram (98:2～95:5EtOAc/2M NH₃MeOH solution) purifying obtains the title compound (61 mg) of yellow solid.

¹H-NMR(CDCl ₃)δ：2.69(s，3H，CH ₃)，2.71(s，3H，CH ₃)，2.84(s，3H，CH ₃)， 3.26(t，4H，J＝5.1Hz，CH ₂)，3.41(t，4H，J＝5.1Hz，CH ₂), 6.91 (d, 1H, J=5.1Hz, pyrimidine radicals-H), and 6.98 (d, 2H, J=8.8Hz, Ph-H), 7.10 (br.s, 1H, NH), 7.56 (d, 2H, J=8.8Hz, Ph-H), 8.30 (d, 1H, J=5.1Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 446(C ₂₀H ₂₄N ₆O ₂S ₂Theoretical value 444.6).

[4-(4-benzyl-piperazine-1-yl)-phenyl]-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-yl]-amine [11]

Partly be dissolved in 4-(4-benzyl-piperazine-1-yl)-phenyl amine (2.17g, 8.12mmol) among the EtOH (5 mL) and drip HNO₃(69% aqueous solution, 1.05mL, 16.32mmol) then adds cyanamide (50% aqueous solution, 1.13mL, 16.32mmol). Mixture was added hot reflux 18 hours. After the post processing, obtain the N-[4-(4-benzyl-piperazine-1-yl)-phenyl into the purple solid]-guanidine nitrate (1.16g). With this material (2.66mmol), 3-dimethylamino-1-(4-methyl-2-methylamino thiazole-5-yl)-propenone (0.60g, 2.66mmol) and K₂CO ₃(0.74g, 5.32mmol) mixture in 2-methyl cellosolve (15mL) was 120 ℃ of heating 18 hours. After the cooling, be poured among the EtOAc (100mL) and filter silicagel pad. Evaporated filtrate, and with residue through SiO₂(heptane/EtOAc) purifying obtains shallow tan title compound (442mg) to chromatogram.

¹H-NMR(CD ₃OD)δ：2.44(s，3H，CH ₃)，2.56-2.58(m，4H，CH ₂)，2.91(s，3H， CH ₃)，3.09(m，4H，CH ₂)，3.51(s，2H，CH ₂), 6.70 (d, 1H, J=5.6Hz, pyrimidine radicals-H), and 6.87 (m, 2H, Ph-H), 7.22 (m, 1H, Ph-H), 7.27 (m, 4H, Ph-H), 7.43 (m, 2H, Ph-H), 8.15 (d, 1H, J=5.4Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 473.2(C ₂₆H ₂₉N ₇S theoretical value 471.6).

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine [12]

Utilize 3-dimethylamino-1-(2,4-dimethyl-thiazole-5-yl)-propenone and N-[4-(4-methyl-piperazine-1-yl)-phenyl]-condensation reaction between the guanidine nitrate prepares. The glassy yellow solid.

¹H-NMR(CDCl ₃)δ：2.37(s，3H，CH ₃)，2.61(m，4H，CH ₂)，2.69(s，3H，CH ₃)， 2.70(s，3H，CH ₃)，3.20(m，4H，CH ₂), 6.88 (d, 1H, J=5.1Hz, pyrimidine radicals-H), and 6.94 (s, 1H, NH), 6.96 (d, 2H, J=8.8Hz, Ph-H), 7.51 (d, 2H, J=8.8Hz, Ph-H), 8.38 (d, 1H, J=5.1Hz, pyrimidine radicals-H).

3-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide [13]

Will [4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(3-nitro-phenyl)-amine (0.12g, 0.37mmol), Boc-β Ala-OH (0.18g, 0.93mmol), 1,3-DIC (0.07mL, 0.45mmol) and 4-N, the mixture room temperature of N-dimethyl aminopyridine (36mg, 0.3mmol) in dry DMF (2mL) stirred 24 hours. Mixture is poured in the water and with EtOAc extracts. Organic layer is merged and use the salt water washing, filtration, and at MgSO₄Upper drying. The evaporation solvent obtains the residue of brown, with it through SiO₂Chromatogram (1:1 EtOAc/PE) purifying obtains glassy yellow solid ({ 4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-base carbamoyl)-methyl)-carbamic acid tert-butyl group ester.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=19.5 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞93%).

¹H-NMR(DMSO-d ₆)δ：1.11(s，9H，CH ₃)，2.54(s，3H，CH ₃)，3.62(m，2H， CH ₂)，5.38(m，2H，CH ₂), 7.06 (d, 1H, J=5.5Hz, pyrimidine radicals-H), and 7.46 (m, 1H, Ph-H), 7.72 (m, 1H, Ph-H), 8.15 (m, 1H, Ph-H), 8.45 (d, 1H, J=5.2Hz, pyrimidine radicals-H), 8.77 (s, 1H, NH).

With this material (solution CF in 97mg, the 0.19mmol) Zai diox (5mL)₃COOH (1ml) processes. Room temperature stirred after 22 hours, evaporation reaction mixture and through preparation property RP-HPLC (0-60% MeCN is at 0.1%aq CF₃Eluant solution among the COOH 40 minutes, 9mL/ minute) purifying obtains being the title compound of glassy yellow solid (34mg).

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=14.0 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞93%).

¹H-NMR(CD ₃OD)δ：2.64(s，3H，CH ₃)，3.30(m，2H，CH ₂)，3.33(m，2H， CH ₂), 7.14 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 7.52 (t, 1H, J=8.2Hz, Ph-H), 7.63 (m, 1H, Ph-H), 7.96 (m, 1H, Ph-H), 8.46 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 8.88 (s, 1H, NH).

MS(ESI ⁺)m/z 400.6(C ₁₇H ₁₇N ₇O ₃S theoretical value 399.4).

(2S)-2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide [14]

Prepare from Boc-L-Ser-OH. Linen solid.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=13.7 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞93%).

¹H-NMR(CD ₃OD)δ：2.45(s，3H，CH ₃)，3.65-3.77(m，3H，CH & CH ₂), 3.95 (br.s, 1H, OH), 7.03 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 7.36 (t, 1H, J=6.5Hz, Ph-H), 7.63 (m, 1H, Ph-H), 7.97 (m, 1H, Ph-H), 8.41 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 8.63 (s, 1H, NH).

(2R, 3R)-2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide [15]

Prepare from Boc-D-Thr-OH. Yellow solid.

¹H-NMR(CD ₃OD)δ：1.35(d，3H，J＝6.1Hz，CH ₃), 2.66 (s, 1H, CH), 3.95 (d, 1H, J=5.4Hz, CH), 7.17 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 7.51 (m, 1H, Ph-H), 7.97 (m, 1H, Ph-H), 8.51 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 8.92 (m, 1H, Ph-H).

(2R)-2-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide [16].

Prepare from Boc-D-Abu-OH. Yellow solid.

¹H-NMR(DMSO-d ₆)δ：0.93(t，3H，J＝7.6Hz，CH ₃)，0.94(m，2H，CH ₂)， 1.60(s，3H，CH ₃), 3.00 (t, 1H, J=6.9Hz, CH), 6.10 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 6.44 (m, 1H, Ph-H), (6.77 m, 1H, Ph-H), 6.87 (m, 1H, Ph-H), 7.42 (d, 1H, J=5.5 Hz, pyrimidine radicals-H) and 7.86 (br.s, 1H, NH).

MS(ESI ⁺)m/z 414.6(C ₁₈H ₁₉N ₇O ₃S theoretical value 413.5).

(2S, 3S)-2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide [17]

Prepare from Boc-L-Thr-OH. Yellow solid.

¹H-NMR(CD ₃OD)δ：1.19(d，3H，J＝6.6Hz，CH ₃)，2.63(s，3H，CH ₃), 3.89 (m, 1H, CH), 4.10 (m, 1H, CH), 7.20 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 7.55 (t, 1H, J=8.0Hz, Ph-H), 7.81 (d, 1H, J=8.5Hz, Ph-H), 8.16 (d, 1H, J=8.5Hz, Ph-H), 8.58 (d, 1H, J=5.5Hz, pyrimidine radicals-H), (8.80 s, 1H, Ph-H) and 10.17 (s, 1H, NH).

4-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide [18].

Yellow solid.

¹H-NMR(CD ₃OD)δ：1.87(m，2H，CH ₂)，2.52(s，3H，CH ₃)，2.56(m，2H， CH ₂)，2.84(m，2H，CH ₂), 7.17 (d, 1H, J=5.3Hz, pyrimidine radicals-H), 7.55 (t, 1H, J=8.3 Hz, Ph-H), 7.79 (m, 1H, Ph-H), (8.13 m, 1H, Ph-H), 8.54 (d, 1H, J=5.3Hz, pyrimidine radicals-H), 8.83 (s, 1H, Ph-H) and 10.12 (s, 1H, NH).

3-amino-N-{4-methyl-5-[2-(4-morpholine-4-base-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide [19].

Yellow solid.

¹H-NMR(DMSO-d ₆)δ：2.57(m，2H，CH ₂)，2.71(s，3H，CH ₃)，2.92(m，2H， CH ₂)，3.02(m，4H，CH ₂)，3.73(m，4H，CH ₂), 6.87 (d, 2H, J=8.0Hz, Ph-H), 6.95 (d, 1H, J=5.3Hz, pyrimidine radicals-H), 7.61 (d, 1H, J=8.0Hz, Ph-H), 8.38 (d, 1H, J=5.5Hz, pyrimidine radicals-H) and 9.32 (s, 1H, NH).

MS(ESI ⁺)m/z 439(C ₂₁H ₂₅N ₇O ₂S theoretical value 439.5).

3-bromo-N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide [20].

Will [4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-fluoro-phenyl)-amine (0.3g, 1.0 mmol) solution in DMF (2mL) is processed in the ice bath cooling and with 2-bromo propionyl chloride (0.17g, 1.0 mmol). After reaction is finished, reactant mixture was stirred 18 hours in room temperature. Be poured in the water and use CH₂Cl ₂Extraction. Merge organic matter, use the salt water washing, at MgSO₄Upper drying, and the evaporation solvent obtains the residue of brown. With it through SiO₂Chromatogram (1: 1 EtOAc/PE) purifying obtains the title compound of glassy yellow solid.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=17.1 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞93%).

¹H-NMR(DMSO-d ₆)δ：1.99(m，2H，CH ₂)，2.68(s，3H，CH ₃)，4.65(m，2H， CH ₂), 7.02 (d, 1H, J=5.2Hz, pyrimidine radicals-H), and 7.11 (m, 2H, Ph-H), 7.62 (m, 2H, Ph-H), 8.19 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-morpholine-4-base-propionamide [21].

With 3-bromo-N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide (20mg, 0.046mmol) and morpholine (8 μ L, 0.092mmol) the solution room temperature in DMF (2mL) stirred 2 hours. (0-60%MeCN is at 0.1%aq CF through preparation property RP-HPLC with reactant mixture₃Eluant solution among the COOH 40 minutes, 9mL/ minute) purifying obtains the title compound of pale asphyxia solid.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=13.3 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞93%).

¹H-NMR(CD ₃OD)δ：2.66(s，3H，CH ₃)，3.23(m，2H，CH ₂)，3.33(m，2H， CH ₂)，3.41(m，4H，CH ₂)，3.87(m，2H，CH ₂)，4.13(m，2H，CH ₂), 7.04-7.09 (m, 3H, pyrimidine radicals-H ﹠ Ph-H), 7.68 (m, 2H, Ph-H), 8.39 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 443.3(C ₂₁H ₂₃FN ₆O ₂S theoretical value 442.5).

N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-3-morpholine-4-base-propionamide [22]

Yellow solid.

¹H-NMR(CD ₃OD)δ：2.64(s，3H，CH ₃)，3.23(m，2H，CH ₂)，3.33(m，2H， CH ₂)，3.41(m，4H，CH ₂)，3.87(m，2H，CH ₂)，4.13(m，2H，CH ₂), 7.04-7.09 (m, 3H, pyrimidine radicals-H ﹠ Ph-H), 7.68 (m, 2H, Ph-H), 8.39 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 443.3(C ₂₁H ₂₃FN ₆O ₂S theoretical value 442.5).

N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-3-(4-methyl-piperazine-1-yl)-propionamide [23]

Yellow solid.

¹H-NMR(CD ₃OD)δ：2.94(s，3H，CH ₃)，3.01(m，2H，CH ₂)，3.24-3.43(m，4H， CH ₂)，3.65(m，2H，CH ₂), 7.14 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 7.52 (m, 1H, Ph-H), (7.86 d, 1H, J=8.0Hz, Ph-H), 7.99 (d, 1H, J=8.0Hz, Ph-H), and 8.44 (m, 1H, Ph-H) and 8.79 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 485(C ₂₂H ₂₆N ₈O ₃S theoretical value 482.6).

2-chloro-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-acetamide [24]

[4-(2-amino-4-methyl-thiazole-5-yl)-the pyrimidine-2-base]-solution of (3-nitro-phenyl)-amine (0.33g, 1.0 mmol) in dry DMF (3mL) is cooled off at ice bath. Add chloro-acetyl chloride (0.22g, 2.0mmol) and pyridine (80 μ L). Room temperature stirred after 18 hours, and reactant mixture is concentrated, was poured in the water and used CH₂Cl ₂Extraction. Merge organic phase, use the salt water washing, at MgSO₄Upper drying also is evaporated to dried. With the green residue that obtains through SiO₂Chromatogram (1: 1 EtOAc/PE) purifying obtains the title compound of gray solid.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=20.6 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞97%).

¹H-NMR(DMSO-d ₆)δ：2.45(s，3H，CH ₃)，4.12(s，2H，CH ₂), 7.03 (d, 1H, J=5.2Hz, pyrimidine radicals-H), and 7.42 (m, 1H, Ph-H), 7.63 (m, 1H, Ph-H), 8.01 (m, 1H, Ph-H), 8.41 (d, 1H, J=5.2Hz, pyrimidine radicals-H), 8.64 (s, 1H, Ph-H).

2-chloro-N-{5-[2-(3-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide [25]

Brown solid.

¹H-NMR(DMSO-d ₆)δ：2.65(s，3H，CH ₃)，4.42(s，2H，CH ₂), 7.01 (m, 1H, Ph-H), 7.25 (m, 1H, Ph-H), 7.61 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 7.98 (s, 1H, Ph-H), 8.75 (d, 1H, J=5.5Hz, pyrimidine radicals-H) and 10.09 (br.s, 1H, NH).

2-chloro-N-{5-[2-(3-methoxyl group-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide [26]

Brown solid.

¹H NMR(DMSO-d ₆)δ：2.58(s，3H，CH ₃)，3.78(s，3H，CH ₃)，4.36(s，2H， CH ₂), 6.51 (m, 1H, Ph-H), 7.08 (d, 1H, J=5.5, pyrimidine radicals-H), 7.14 (t, 1H, J=8.0Hz, Ph-H), 7.23 (m, 1H, Ph-H), and 7.59 (s, 1H, Ph-H) and 8.45 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

2-chloro-N-{5-[2-(4-dimethylamino-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide [27]

Yellow solid.

¹H-NMR(CD ₃OD)δ：2.57(s，3H，CH ₃)，3.23(s，6H，CH ₃)，4.22(s，2H，CH ₂), 7.06 (d, 1H, J=5.5Hz, pyrimidine radicals-H), and 7.57 (d, 2H, J=9.5Hz, Ph-H), 7.73 (d, 2H, J=9.5Hz, Ph-H), 8.14 (br.s, 1H, NH) and 8.35 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

4-(4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-base carbamoyl }-methyl)-piperazine-1-carboxylic acid tert-butyl group ester [28]

With 2-chloro-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-solution of acetamide (40mg, 0.1mmol) in DMF (2mL) cools off at ice bath. Add piperazine-1-carboxylic acid tert-butyl group ester (40mg, 0.21mmol). Room temperature stirred after 16 hours, and (0-60%MeCN is at 0.1%aq CF through preparation property RP-HPLC with reactant mixture₃Eluant solution among the COOH 40 minutes, 9mL/ minute) purifying obtains the title compound (20mg) of glassy yellow solid.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=16.9 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞97%).

¹H-NMR(CD ₃OD)δ：2.65(s，3H，CH ₃)，2.87(m，4H，CH ₂)，3.36(m，4H， CH ₂)，4.66(s，2H，CH ₂), 7.71 (m, 1H, pyrimidine radicals-H), 7.89 (t, 1H, J=8.1Hz, Ph-H), 8.15 (m, 1H, Ph-H), 7.42 (m, 1H, Ph-H), 7.67 (m, 2H, pyrimidine radicals-H ﹠ Ph-H).

N-{5-[2-(4-dimethylamino-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-2-[2-(2-hydroxyl-ethyoxyl)-ethyl is amino]-acetamide [29]

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=10.52 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞97%).

¹H-NMR(CD ₃OD)δ：3.28(s，3H，CH ₃)，3.41(s，6H，CH ₃)，4.04(m，2H，CH ₂)， 4.28(m，2H，4H，CH ₂)，4.34(m，2H，CH ₂)，4.50(m，2H，CH ₂)，4.94(br.s，2H，CH ₂), 7.92 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 8.00 (d, 2H, J=9.0Hz, Ph-H), 8.41 (m, 1H, J=9.0Hz, Ph-H), 8.87 (b r.s, 1H, NH/OH), 9.31 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

6-[5-(2-oxo-six hydrogen-thieno [3,4-d] imidazoles-4-yl)-valeryl is amino]-caproic acid (2-{4-methyl-5-[2-(4-morpholine-4-base-phenyl amino)-pyrimidine-4-yl]-thiazole-2-base carbamoyl }-ethyl)-acid amides [30]

With 3-amino-N-{4-methyl-5-[2-(4-morpholine-4-base-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide (75mg, 0.17mmol) solution in DMF (1mL) processes with succinimido-6-(biotin acid amides) capronate (32mg, 0.085mmol). Room temperature stirred after 3 hours, and (0-60%MeCN is at 0.1%aq CF through preparation property RP-HPLC for reactant mixture₃Eluant solution among the COOH 40 minutes, 9mL/ minute) purifying obtains the title compound of orange solids.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=13.2 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞97%).

MS(ESI+)m/z 776(C ₃₇H ₅₀N ₁₀O ₅S ₂Theoretical value 778.9).

N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-Methanesulfomide [31]

This compound utilizes methylsufonyl chloride and Et₃N processes [4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-fluoro-phenyl)-amine and prepares in DMF. Gray solid.

¹H-NMR(DMSO-d ₆)δ：3.31(s，3H，CH ₃)，3.63(s，3H，CH ₃), 7.32 (m, 1H, pyrimidine radicals-H), and 7.42 (m, 2H, Ph-H), 8.11 (m, 2H, Ph-H), 8.63 (d, 1H, J=5.0Hz, pyrimidine radicals-H).

N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-Methanesulfomide [32]

In [4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(3-nitro-phenyl)-amine (1.0mmol, 0.33g) and the mixture of methylsufonyl chloride (2.0mmol, 0.22g) in dry DMF (2mL), add Et₃N (0.28mL). The reactant mixture room temperature was stirred 20 hours. After the cooling, mixture is diluted with EtOAc, use the salt water washing, and at MgSO₄Upper drying. The evaporation solvent and with residue through preparation property RP-HPLC purifying, utilize the 0.1%aq CF from 10-70%MeCN₃COOH eluant solution 40 minutes. Obtain the title compound of orange solids.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=17.4 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞97%).

¹H-NMR(DMSO-d ₆)δ：3.10(s，3H，CH ₃)，3.25(s，3H，CH ₃), 7.05 (d, 1H, J=5.2Hz, pyrimidine radicals-H), 7.42 (m, 1H, Ph-H), (7.63 m, 1H, Ph-H), 7.98 (m, 1H, Ph-H), 8.21 (d, 1H, J=5.2Hz, pyrimidine radicals-H), 8.42 (s, 1H, Ph-H), 9.18 (s, 1H, NH).

2-chloro-N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide [33].

This compound prepares from [4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-fluoro-phenyl)-amine.

¹H-NMR(DMSO-d ₆)δ：2.94(s，3H，CH ₃)，4.75(s，2H，CH ₂), 7.44 (m, 3H, pyrimidine radicals-H ﹠ Ph-H), 8.09 (m, 2H, Ph-H), 8.28 (s, 1H, NH), 8.80 (d, 1H, J=5.2Hz, pyrimidine radicals-H).

2-chloro-N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide [34]

This compound utilizes the chloro acetylation of [4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-chloro-phenyl)-amine to prepare. Brown solid.

¹H-NMR(DMSO-d ₆)δ：2.65(s，3H，CH ₃)，4.42(s，2H，CH ₂), 7.01 (m, 1H, Ph-H), 7.25 (m, 1H, Ph-H), 7.61 (d, 1H, J=5.5, pyrimidine radicals-H), 7.98 (s, 1H, Ph-H), 8.75 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 10.09 (br.s, 1H, NH).

N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl)-3-morpholine-4-base-propionamide [35].

With 3-chloro-N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide processes with morpholine.

Analyze RP-HPLC:t_R=12.7 minutes (10-70%MeCN, purity＞95%).

¹H-NMR(CDCl ₃)δ：1.50(m，2H，CH ₂)，2.52(s，3H，CH ₃)，3.05-3.78(m，8H， CH ₂)，3.81(m，2H，CH ₂), 7.12 (d, 1H, J=5.5Hz, pyrimidine radicals-H), and 7.30 (d, 2H, J=7.0Hz, Ph-H), 7.80 (d, 2H, J=7.0Hz, Ph-H), 8.51 (d, 1H, J=5.0Hz, pyrimidine radicals-H), 9.80 (brs, 1H, NH).

N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-(2-diethylamino-ethyl is amino)-propionamide [36].

With 3-bromo-N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide N1, N1-diethyl-ethane-1, the 2-diamines is processed.

Analyze RP-HPLC:t_R=11.8 minutes (10-70%MeCN, purity＞97%).

¹H-NMR(DMSO-D ₆)δ：1.20(t，6H，J＝7.0Hz，CH ₃)，1.53(d，2H，J＝6.5Hz， CH ₂)，2.52(s，6H，CH ₃)，3.18(m，4H，CH ₂)，3.28(m，4H，CH ₂), 7.13 (d, 1H, J=5.0Hz, pyrimidine radicals-H), and 7.30 (m, 2H, Ph-H), 7.81 (m, 2H, Ph-H), 8.51 (d, 1H, J=5.0 Hz, pyrimidine radicals-H), 9.82 (brs, 1H, NH).

N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-(2-morpholine-4-base-ethyl is amino)-propionamide [37].

With 3-bromo-N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide 2-morpholine-4-base-ethylamine processing (perhaps with 3-amino-N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide 4-(2-chloro-ethyl)-morpholine processing.

Analyze RP-HPLC:t_R=11.5 minutes (10-70%MeCN, purity＞97%).

¹H-NMR(DMSO-D ₆)δ：1.52(d，2H，J＝7.0Hz，CH ₂)，2.48(m，2H，CH ₂)， 2.52(s，3H，CH ₃)，3.05-3.11(m，4H，CH ₂)，3.25-3.28(m，6H，CH ₂)，4.08(m，2H， CH ₂), 7.13 (d, 1H, J=5.5Hz, pyrimidine radicals-H), and 7.29 (m, 2H, Ph-H), 7.82 (m, 2H, Ph-H), 8.51 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 9.82 (brs, 1H, NH).

N-{5-[2-(4-methoxyl group-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-morpholine-4-base-propionamide [38].

With 3-bromo-N-{5-[2-(4-methoxyl group-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide processes with morpholine.

Analyze RP-HPLC:t_R=12.7 minutes (0-60%MeCN, purity＞90%).

¹H-NMR(CDCl ₃)δ：1.20(m，2H，CH ₂)，2.54-2.63(m，7H，CH ₃ and CH ₂)， 3.34(m，2H，CH ₂)，3.80(m，5H，CH ₃ and o)，4.03(m，2H，CH ₂), 6.87-6.92 (m, 3H, pyrimidine radicals-H and Ph-H), 7.17 (brs, 1H, NH), 7.53 (m, 2H, Ph-H), 8.35 (m, 1H, pyrimidine radicals-H), 10.33 (brs, 1H, NH).

N-{5-[2-(3-methoxyl group-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-morpholine-4-base-propionamide [39].

With 3-bromo-N-{5-[2-(3-methoxyphenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide processes with morpholine.

Analyze RP-HPLC:t_R=13.6 minutes (0-60%MeCN, purity＞94%).

¹H-NMR(DMSO-D ₆)δ：1.20(m，2H，CH ₂)，2.48(m，4H，CH ₂)，2.58(s，3H， CH ₃)，3.41-3.57(m，6H，CH ₂)，3.79(s，3H，CH ₃), 6.52 (d, 1H, J=7.0Hz, Ph-H), 7.07 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 7.15 (t, 1H, J=7.3Hz, Ph-H), 7.22 (m, 1H, Ph-H), 7.62 (brs, 1H, Ph-H), 8.46 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 9.58 (brs, 1H, NH).

MS(ESI ⁺)m/z 456.01[M+H] ⁺(C ₂₂H ₂₆N ₆SO ₃Theoretical value 454.55).

N-{5-[2-(4-methoxyl group-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-(4-methyl-piperazine-1-yl)-propionamide [40].

With 3-bromo-N-(5-[2-(4-methoxyphenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide is with 1-methyl-piperazine processing.

Analyze RP-HPLC:t_R=13.0 minutes (0-60%MeCN, purity＞94%).

¹H-NMR(DMSO-D ₆)δ：1.17(m，2H，CH ₂)，2.11(m，2H，CH ₂)，2.48(m，4H， CH ₂)，2.57(s，3H，CH ₃)，3.28(s，3H，CH ₃)，3.30(m，4H，CH ₂)，3.72(s，3H，CH ₃), 6.85 (m, 2H, Ph-H), 6.97 (m, 1H, pyrimidine radicals-H), 7.63 (m, 2H, Ph-H), 8.38 (d, 1H, J=5.1Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 468.57[M+H] ⁺(C ₂₃H ₂₆N ₇SO ₂Theoretical value 467.59).

N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-acetamide [45].

Utilize the condensation reaction between 3-dimethylamino-1-(2,4-dimethyl-thiazole-5-yl)-propenone and N-(4-acetamido the phenyl)-guanidine nitrate to prepare. Linen solid. Mp.219-220 ℃.

¹H-NMR(DMSO-D ₆)δ：2.00(s，3H，CH ₃)，2.61(s，3H，CH ₃)，2.64(s，3H， CH ₃), 7.04 (d, 1H, J=4.9Hz, pyrimidine radicals-H), 7.48 (d, 2H, J=8.8Hz, Ph-H), 7.64 (d, 2H, J=8.8Hz, Ph-H), 8.47 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 9.58 (s, 1H, NH), 9.82 (s, 1H, NH).

MS(ESI ⁺)m/z 340.02[M+H] ⁺(C ₁₇H ₁₇N ₅OS theoretical value 339.42).

N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-N-methyl-acetamide [48].

Utilize the condensation reaction between 3-dimethylamino-1-(2,4-dimethyl-thiazole-5-yl)-propenone and N-(4-N-methylacetamide base phenyl)-guanidine nitrate.

¹H-NMR(DMSO-D ₆)δ：1.75(s，3H，CH ₃)，2.62(s，3H，CH ₃)，2.64(s，3H， CH ₃)，3.11(s，3H，CH ₃), 7.11 (d, 1H, J=4.9Hz, pyrimidine radicals-H), and 7.24 (d, 2H, J=7.8Hz, Ph-H), 7.83 (d, 2H, J=7.8Hz, Ph-H), 8.53 (d, 1H, J=4.9Hz, pyrimidine radicals-H), 9.83 (brs, 1H, NH).

MS(ESI ⁺)m/z 354.88[M+H] ⁺(C ₁₈H ₁₉N ₅OS theoretical value 353.44).

1-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-propan-2-ol [49].

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-piperazine-1-base-phenyl)-amine is processed with 1-chloro-2-propyl alcohol.

¹H-NMR(CDCl ₃)δ：1.10(d，3H，J＝6.0Hz，CH ₃)，2.26-2.33(m，2H，CH ₂)， 2.49-2.53(m，2H，CH ₂)，2.61(s，3H，CH ₃)，2.63(s，3H，CH ₃)，2.76-2.80(m，2H， CH ₂)，3.07-3.13(m，4H，CH ₂), 3.83 (m, 1H, CH), 6.81 (d, 1H, J=4.4Hz, pyrimidine radicals-H), (6.88 d, 2H, J=8.8Hz, Ph-H), 7.02 (brs, 1H, OH), 7.44 (d, 2H, J=8.8Hz, Ph-H), 8.30 (d, 1H, J=4.4Hz, pyrimidine radicals-H).

2-chloro-N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-acetamide [50].

[4-(2,4-dimethylthiazole-5-yl)-pyrimidine-2-base]-(4-aminophenyl)-amine is processed with chloro-acetyl chloride. Mp.217-219 ℃.

¹H-NMR(DMSO-D ₆)δ：2.61(s，3H，CH ₃)，2.64(s，3H，CH ₃)，4.22(s，2H， CH ₂), 7.05 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 7.50 (d, 2H, J=8.8Hz, Ph-H), 7.70 (d, 2H, J=8.8Hz, Ph-H), 8.49 (d, 1H, J=4.9Hz, pyrimidine radicals-H), 9.65 (s, 1H, NH), 10.20 (s, 1H, NH).

MS(ESI ⁺)m/z 374.47[M+H] ⁺(C ₁₇H ₁₆ClN ₅OS theoretical value 373.86).

N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-2-morpholine-4-base-acetamide [51].

With 2-chloro-N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-acetamide processes with morpholine.

¹H-NMR(DMSO-D ₆)δ：2.61(s，3H，CH ₃)，2.64(s，3H，CH ₃)，3.09(s，2H， CH ₂)，3.27-3.31(m，4H，CH ₂)，3.62-3.64(m，4H，CH ₂), 7.04 (d, 1H, J=5.4Hz, pyrimidine radicals-H), and 7.54 (d, 2H, J=8.8Hz, Ph-H), 7.67 (d, 2H, J=8.8Hz, Ph-H), 8.48 (d, 1H, J=4.9Hz, pyrimidine radicals-H), 9.59 (s, 1H, NH).

MS(ESI ⁺)m/z 425.01[M+H] ⁺(C ₂₁H ₂₄N ₆O ₂S theoretical value 424.52).

N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-2-[1,2,4] triazole-1-base-acetamide [52].

With 2-chloro-N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-acetamide 1H-[1,2,4] the triazole processing.

¹H-NMR(DMSO-D ₆)δ：2.61(s，3H，CH ₃)，2.63(s，3H，CH ₃)，5.10(s，2H， CH ₂), 7.05 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 7.50 (d, 2H, J=8.3Hz, pyrimidine radicals-H), 7.69 (d, 2H, J=8.9Hz, Ph-H), 7.98 (s, 1H, aryl-H), 8.48 (d, 1H, J=4.9Hz, pyrimidine radicals-H), 8.53 (s, 1H, aryl-H), 9.62 (brs, 1H, NH), 10.30 (brs, 1H, NH).

MS(ESI ⁺)m/z 406.97(C ₁₉H ₁₈N ₈OS theoretical value 406.47).

N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-2-pyrrolidin-1-yl-acetamide [53].

With 2-chloro-N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-acetamide processes with pyrrolidines.

¹H-NMR(DMSO-D ₆)δ：1.74(m，4H，CH ₂)，2.58(m，4H，CH ₂)，2.61(s，3H， CH ₃)，2.64(s，3H，CH ₃)，3.20(s，2H，CH ₂), 7.04 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 7.55 (d, 2H, J=8.8Hz, Ph-H), 7.66 (d, 2H, J=8.8Hz, Ph-H), 8.48 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 9.55 (s, 1H, NH), 9.58 (s, 1H, NH).

MS(ESI ⁺)m/z 406.97[M+H] ⁺(C ₂₁H ₂₄N ₆OS theoretical value 408.52).

N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-2-imidazoles-1-base-acetamide [54].

Will be with 2-chloro-N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-acetamide processes with the 1H-imidazoles.

¹H-NMR(DMSO-D ₆)δ：2.61(s，3H，CH ₃)，2.63(s，3H，CH ₃)，4.86(s，2H， CH ₂), 6.88 (s, 1H, aryl-H), 7.04 (d, 1H, J=5.9Hz, pyrimidine radicals-H), 7.15 (s, 1H, aryl-H), 7.50 (d, 2H, J=7.8Hz, Ph-H), 7.62 (s, 1H, aryl-H), 7.68 (d, 2H, J=7.8Hz, Ph-H), 8.48 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 9.60 (s, 1H, NH), 10.18 (brs, 1H, NH).

MS(ESI ⁺)m/z 406.02[M+H] ⁺(C ₂₀H ₁₉N ₇OS theoretical value 405.48).

3-[4-(4-methyl-2-morpholine-4-base-thiazole-5-yl)-pyrimidine-2--amino]-phenol [55].

The solution of morpholine-4-nitrile (10g, 89.19mmol) in EtOH (65mL) is cooled off at ice bath. With anhydrous NH₃Bubbling passed into solution 5 minutes, then passed into hydrogen sulfide. Import H₂Soon observe the precipitation of white behind the S. Add again two kinds of gases 45 minutes, and stopped to add NH₃With H₂S continues to add 15 minutes. Collect the precipitation that forms, also obtain morpholine-4-carbothioic acid acid amides (12.83g) under the high vacuum again with cold water, MeOH washing.

Mp.173-174℃。

¹H-NMR(DMSO-D ₆)δ：3.54(t，4H，J＝4.9Hz，CH ₂)，3.70(m，4H，CH ₂)， 7.46(brs，2H，NH ₂)。

It is at first utilized 3-bromo-pentane-2, the 4-diketone is processed and is changed into 1-(4-methyl-2-morpholine-4-base-thiazole-5-yl)-ethyl ketone, then processes obtaining 3-dimethylamino-1-(4-methyl-2-morpholine-4-base-thiazole-5-yl)-propenone with dimethoxy-methyl-dimethyl-amine according to common mode. Latter's ketones with Enamino-esters and N-(3-hydroxyl-phenyl)-guanidine nitrate condensation obtains the title compound of linen solid.

Mp.227-229C。

¹H-NMR(DMSO-D ₆)δ：2.49(s，3H，CH ₃)，3.46(t，4H，J＝4.4Hz，CH ₂), 3.71 (t, 4H, J=4.4Hz, pyrimidine radicals-H), (6.34 d, 1H, J=8.8Hz, Ph-H), 6.91 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 7.03 (t, 1H, J=7.8Hz, Ph-H), 7.20-7.22 (m, 2H, Ph-H), 8.34 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 9.17 (s, 1H, OH/NH), 9.32 (s, 1H, NH/OH).

MS(ESI ⁺)m/z 370.10[M+H] ⁺(C ₁₈H ₁₉N ₅O ₂S theoretical value 369.44).

[4-(4-methyl-2-morpholine-4-base-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine [56].

3-dimethylamino-1-(4-methyl-2-morpholino-thiazole-5-yl)-propenone is processed with N-(4-morpholino phenyl)-guanidine nitrate. Linen solid. Mp.229-231 ℃.

¹H-NMR(DMSO-D ₆)δ：2.48(s，3H，CH ₃)，3.02(t，4H，J＝4.0Hz，CH ₂)， 3.46(t，4H，J＝4.0Hz，CH ₂)，3.70-3.73(m，8H，CH ₂), 6.86 (d, 1H, J=5.4Hz, pyrimidine radicals-H), and 6.89 (d, 2H, J=9.3Hz, Ph-H), 7.60 (d, 2H, J=8.8Hz, Ph-H), 8.30 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 9.22 (s, 1H, NH).

MS(ESI ⁺)m/z 439.03[M+H] ⁺(C ₂₂H ₂₆N ₆O ₂S theoretical value 438.55).

N, N-dimethyl-N '-[4-(4-methyl-2-morpholine-4-base-thiazole-5-yl)-pyrimidine-2-base]-benzene-Isosorbide-5-Nitrae-diamines [57].

Process 3-dimethylamino-1-(4-methyl-2-morpholino-thiazole-5-yl)-propenone and N-(4-N, N-dimethylaminophenyl)-guanidine nitrate. Yellow solid.

¹H-NMR(DMSO-D ₆)δ：2.48(s，3H，CH ₃)，2.82(s，6H，CH ₃), 3.46 (t, 4H, J=4.9Hz, pyrimidine radicals-H), 3.70 (t, 4H, J=4.9Hz, CH₂), 6.70 (d, 2H, J=8.8Hz, Ph-H), 6.82 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 7.53 (d, 2H, J=8.8Hz, Ph-H), 8.27 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 9.09 (s, 1H, NH).

MS(ESI ⁺)m/z 397.03[M+H] ⁺(C ₂₀H ₂₄N ₆OS theoretical value 396.51).

2-{4-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-ethanol [59].

Utilize 3-dimethylamino-1-(4-methyl-2-methylamino-thiazole-5-yl)-propenone and N-[4-(2-hydroxyl-ethyl)-phenyl]-condensation reaction between the guanidine nitrate prepares. Linen solid.

Mp 216-218℃。

Analyze RP-HPLC:t_R=9.1 minutes (10-70%MeCN, purity＞95%).

¹H-NMR(DMSO-d ₆)δ：2.46(s，3H，CH ₃)，3.05(s，3H，CH ₃)，3.55(m，2H， CH ₂)，4.58(m，2H，CH ₂), 6.85 (d, 1H, J=5.5Hz, pyrimidine radicals-H), and 7.08 (m, 2H, Ph-H), 7.64 (m, 2H, Ph-H), 8.01 (m, 1H, OH), 8.29 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 9.30 (brs, 1H, NH).

MS(ESI ⁺)m/z 363.99[M+H] ⁺Na(C ₁₇H ₁₉N ₅SONa theoretical value 364.43).

1-(4-{4-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-ethyl ketone [61].

Utilize 3-dimethylamino-1-(4-methyl-2-methylamino-thiazole-5-yl)-propenone and N-[4-(4-acetyl group-piperazine-1-yl)-phenyl]-condensation reaction between the guanidine nitrate prepares. Yellow solid.

Mp 213-214℃。

Analyze RP-HPLC:t_R=8.8 minutes (10-70%MeCN, purity＞95%).

¹H-NMR(DMSO-d ₆)δ：2.43(s，3H，CH ₃)，3.02(s，3H，CH ₃)，3.23(s，3H， CH ₃)，2.99(m，2H，CH ₂)，3.06(t，2H，CH ₂)，3.57(t，4H，CH ₂), 6.82 (d, 1H, J=6.0 Hz, pyrimidine radicals-H), and 6.89 (d, 2H, J=9.0Hz, Ph-H), 7.62 (d, 2H, J=9.5Hz, Ph-H), 8.26 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 9.18 (s, 1H, NH).

MS(ESI ⁺)m/z 424.07[M+H] ⁺(C ₂₁H ₂₅N ₇OS theoretical value 423.54).

[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-base]-(4-piperazine-1-base-phenyl)-amine [62].

By 1-(4-{4-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-phenyl-piperazine-1-yl)-ethyl ketone is hydrolyzed in 2M aq HCl.

Yellow solid.

Analyze RP-HPLC:t_R=8.8 minutes (10-70%MeCN, purity＞95%).

¹H-NMR(DMSO-d ₆)δ：2.45(3，3H，CH ₃)，2.83(t，4H，J＝5.9Hz，CH ₂)， 2.85(d，3H，J＝4.9Hz，CH ₂)，2.95(t，4H，J＝4.9Hz，CH ₂), 6.81 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 6.85 (d, 2H, J=9.3Hz, Ph-H), 7.58 (d, 2H, J=8.8Hz, Ph-H), 7.99 (m, 1H, NH), 8.26 (d, 1H, J=5.4Hz, pyrimidine radicals-H), 9.14 (brs, 1H).

N-{3-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-acetamide [63].

By condensation 3-dimethylamino-1-(2-methylamino-4-methyl-thiazole-5-yl)-propenone and N-(3-guanidine radicals-benzyl)-acetamide nitrate. Yellow solid.

Mp 253-255℃。

Analyze RP-HPLC:t_R=11.3 minutes (10-70%MeCN, purity＞95%):

¹H NMR(DMSO)：δ1.86(s，3H，CH ₃)，2.46(s，3H，CH ₃)，2.85(s，2H，CH ₂)， 3.09(s，3H，CH ₃), 6.82 (d, 1H, J=8.0Hz, ph-H), 6.88 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 7.2 (t, 1H, J=8.0Hz, Ph-H), 7.60 (d, 1H, J=8.0Hz, Ph-H), 7.73 (s, 1H, Ph-H), with 8.32 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 391.55[M+Na](C ₁₈H ₂₀N ₆OSNa theoretical value 391.46).

N-{3-[4-(2-ethyl amino-4-methyl-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-acetamide [64].

By condensation 3-dimethylamino-1-(2-ethyl amino-4-methyl-thiazole-5-yl)-propenone and N-(3-guanidine radicals-benzyl)-acetamide nitrate. Yellow solid.

Analyze RP-HPLC:t_R=12.7 minutes (0-60%MeCN, purity＞95%).

¹H-NMR(CD ₃OD)δ：1.17(t，3H，J＝7.5Hz，CH ₃)，1.98(s，3H，CH ₃)， 2.51(s，3H，CH ₃)，3.36(q，2H，J＝7.1Hz，CH ₂)，4.39(s，2H，CH ₂), 6.92 (m, 2H, pyrimidine radicals-H and Ph-H), 7.25 (t, 1H, J=7.6Hz, Ph-H), 7.49 (m, 1H, Ph-H), 7.79 (sbr, 1H, Ph-H), 8.25 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 383.46[M+H] ⁺(C ₁₉H ₂₂N ₆OS theoretical value 382.48).

(3-amino methyl-phenyl)-[4-(2-ethyl amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-amine [65].

By hydrolysis N-{3-[4-(2-ethyl amino-4-methyl-thiazole-5-yl)-pyrimidine-2--amino]-benzyl-acetamide. Yellow solid.

Mp 290-292℃。

Analyze RP-HPLC:t_R=10.6 minutes (10-70%MeCN, purity＞95%).

¹H-NMR(DMSO-D ₆)δ：1.31(t，3H，J＝7.0Hz，CH ₃)，2.64(s，3H，CH ₃)， 3.54(m，2H，CH ₂)，4.11(m，2H，CH ₂), 7.14 (d, 1H, J=6.0Hz, pyrimidine radicals-H), 7.22 (d, 1H, J=8.0Hz, Ph-H), 7.45 (t, 1H, J=8.0Hz, Ph-H), 7.74 (d, 1H, J=8.0Hz, Ph-H), 7.95 (s, 1H, Ph-H), 8.53 (d, 1H, J=6.0Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 341.20[M+H] ⁺(C ₁₇H ₂₀N ₆S theoretical value 340.45).

N-{3-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-acetamide [66].

Process 3-dimethylamino-1-(2,4-dimethyl-thiazole-5-yl)-propenone and N-(3-guanidine radicals-benzyl)-acetamide nitrate. Yellow solid.

Mp 206-207℃。

Analyze RP-HPLC:t_R=13.6 minutes (0-60%MeCN, purity＞95%).

¹H-NMR(DMSO-D ₆)δ：1.99(s，3H，CH ₃)，2.65(s，3H，CH ₃)，2.68(s，3H， CH ₃)，4.38(s，2H，CH ₂), 6.94 (d, 1H, J=7.5Hz, Ph-H), 7.01 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 7.26 (d, 1H, J=8.0Hz, Ph-H), 7.56 (d, 1H, J=7.5Hz, Ph-H), 7.70 (s, 1H, Ph-H), 8.40 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 345.42[M+H] ⁺(C ₁₈H ₁₉N ₅OS theoretical value 353.44).

(3-amino methyl-phenyl)-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-base]-amine [67].

With N-{3-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-acetamide processes with HCl/MeOH. Yellow solid. Mp 287-289 ℃.

Analyze RP-HPLC:t_R=10.1 minutes (0-60%MeCN, purity 92%).

¹H-NMR(DMSO-D ₆)δ：2.68(s，3H，CH ₃)，3.17(s，3H，CH ₃)，4.17(m，2H， CH ₂), 7.23 (d, 1H, J=6.0Hz, pyrimidine radicals-H), 7.27 (d, 1H, J=8.0Hz, Ph-H), 7.50 (t, 1H, J=8.0Hz, Ph-H), 7.70 (d, 1H, J=7.5Hz, Ph-H), 7.75 (s, 1H, Ph-H), 8.44 (d, 1H, J=6.0Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 327.37[M+H] ⁺(C ₁₆H ₁₈N ₆S theoretical value 326.42).

3-[4-(2-ethyl amino-4-methyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-methyl alcohol [68].

By condensation 3-dimethylamino-1-(2-ethyl amino-4-methyl-thiazole-5-yl)-propenone and N-(3-hydroxymethyl-phenyl)-guanidine nitrate. Yellow solid.

Analyze RP-HPLC:t_R=12.6 minutes (0-60%MeCN, purity＞95%).

¹H-NMR(CD ₃OD)δ：1.28(t，3H，J＝7.3Hz，CH ₃)，2.52(s，3H，CH ₃)，3.35(q， 2H，J＝7.1Hz，CH ₂)，4.63(s，2H，CH ₂), 5.49 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 7.63 (d, 1H, J=7.6Hz, Ph-H), 7.27 (t, 1H, J=7.9Hz, Ph-H), 7.52 (m, 1H, Ph-H), (7.79 sbr, 1H, Ph-H), 8.26 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 346.44[M+H] ⁺(C ₁₇H ₁₉N ₅OS theoretical value 341.43).

[4-(4-methyl-2-morpholine-4-base-thiazole-5-yl)-pyrimidine-2-base]-(3-nitro-phenyl)-amine [71].

By condensation 3-dimethylamino-1-(4-methyl 2-morpholine-4-base-thiazole-5-yl)-propenone and N-(3-nitro-phenyl)-guanidine nitrate. Yellow solid.

Analyze RP-HPLC:t_R=16.7 minutes (10-70%MeCN, purity＞95%).

¹H-NMR(DMSO-D ₆)δ：2.51(s，3H，CH ₃)，3.50(t，4H，J＝4.5Hz，CH ₂)， 3.72(t，4H，J＝4.5Hz，CH ₂), 7.06 (d, 1H, J=5.5Hz, pyrimidine radicals-H), (7.55 t, 1H, J=8.5Hz, Ph-H), 7.77 (d, 1H, J=8.5Hz, Ph-H), 7.97 (d, 1H, J=8.5Hz, Ph-H), 8.44 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 9.03 (s, 1H, Ph-H), 10.06 (sbr, 1H, NH).

MS(ESI ⁺)m/z 399.20[M+H] ⁺(C ₁₈H ₁₈N ₆O ₃S theoretical value 398.44).

2-chloro-5-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-methyl alcohol [72].

By condensation 3-dimethylamino-1-(2,4-dimethyl-thiazole-5-yl)-propenone and N-(4-chloro-3-hydroxymethyl-phenyl)-guanidine nitrate. Yellow solid. Mp 245-246 ℃.

Analyze RP-HPLC:t_R=14.6 minutes (10-70%MeCN, purity＞95%).

¹H-NMR(DMSO-D ₆)δ：2.62(s，3H，CH ₃)，2.63(s，3H，CH ₃)，4.53(d，2H，J＝ 5.5Hz，CH ₂), 5.34 (m, 1H, OH), 7.08 (d, 1H, J=5.5Hz, pyrimidine radicals-H), (7.29 m, 1H, Ph-H), 7.73 (m, 1H, Ph-H), 7.94 (s, 1H, Ph-H), 8.51 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 9.78 (s, 1H, NH).

MS(ESI ⁺)m/z 347.11[M+H] ⁺(C ₁₆H ₁₅ClN4 _OS theoretical value 346.84).

2-chloro-5-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-methyl alcohol [73].

By condensation 3-dimethylamino-1-(2-methylamino-4-methyl-thiazole-5-yl)-propenone and N-(4-chloro-3-hydroxyl methyl-phenyl)-guanidine nitrate. Yellow solid. Mp 191-193 ℃.

Analyze RP-HPLC:t_R=11.5 minutes (10-70%MeCN, purity＞90%).

¹H-NMR(DMSO-D ₆)δ：2.46(s，3H，CH ₃)，3.08(s，3H，CH ₃)，4.52(d，2H，J＝ 6.0Hz，CH ₂), 5.29 (m, 1H, OH), 6.89 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 7.25 (d, 1H, J=8.5Hz, Ph-H), 7.73 (m, 1H, Ph-H), (7.94 s, 1H, Ph-H), 8.03 (sbr, 1H, NH), 8.32 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 9.55 (s, 1H, NH).

MS(ESI ⁺)m/z 361.89[M](C ₁₆H ₁₆ClN ₅OS theoretical value 361.85).

[4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-mesyl-phenyl)-amine [76].

By condensation N '-[5-(3-dimethylamino-acryloyl group)-4-methyl-thiazole-2-yl]-N, N-dimethyl-carbonamidine and N-(4-mesyl-phenyl)-guanidine nitrate. Yellow solid.

Analyze RP-HPLC:t_R=13.2 minutes (0-60%MeCN, purity＞97%).

¹H-NMR(DMSO-d ₆)δ：1.98(s，3H，CH ₃)，2.54(s，3H，CH ₃), 7.06 (d, 1H, J=5.5Hz, pyrimidine radicals-H), and 7.80 (m, 2H, Ph-H), 8.00 (m, 2H, Ph-H), 8.45 (d, 1H, J=5.5 Hz, pyrimidine radicals-H), 10.05 (sbr, 2H, NH₂)。

MS(ESI ⁺)m/z 362.38[M+H] ⁺(C ₁₅H ₁₅N ₅O ₂S ₂Theoretical value 361.44).

[4-(2-methoxyl group-ethyoxyl)-3-nitro-phenyl]-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-base]-amine [77].

By with 2-methoxyl group-ethanol alkylation [4-(2-amino methyl-4-methyl-thiazole-5-yl)-pyrimidine-2-yl]-(4-fluoro-3-nitrobenzophenone)-amine. Yellow solid.

Analyze RP-HPLC:t_R=12.8 minutes (10-70%MeCN, purity＞90%).

¹H-NMR(DMSO-D ₆)δ：2.41(s，3H，CH ₃)，2.86(d，3H，J＝4.5Hz，CH ₃)， 3.24(s，3H，CH ₃)，3.66(m，2H，CH ₂)，4.23(m，2H，CH ₂), 6.93 (d, 1H, J=6.0Hz, pyrimidine radicals-H), (7.32 d, 1H, J=5.0Hz, Ph-H), 7.79 (m, 1H, Ph-H), 8.08 (d, 1H, J=5.0 Hz, Ph-H), 8.35 (d, 1H, J=5.0Hz, pyrimidine radicals-H), 8.54 (m, 1H, NH), 9.68 (s, 1H, NH).

MS(ESI ⁺)m/z 417.08[M+H] ⁺(C ₁₈H ₂₀N ₆O ₄S theoretical value 416.46).

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[3-(2-morpholine-4-base-ethoxyl methyl)-phenyl]-amine [81].

By utilizing 4-(2-chloro-ethyl)-morpholine alkylation { 3-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-methyl alcohol. Yellow solid.

Analyze RP-HPLC:t_R=8.5 minutes (10-70%MeCN, purity＞95%).

¹H-NMR(DMSO-D ₆)δ：2.56(s，3H，CH ₃)，2.57(s，3H，CH ₃)，2.63(m，2H， CH2)，3.58(m，4H，J＝4.5Hz，CH ₂x2)，4.14(t，2H，J＝7.5Hz，CH ₂)，4.58(d，2H， J＝5.0Hz，CH ₂), 5.28 (t, 1H, J=5.5Hz, NH), 7.06 (d, 1H, J=5.5Hz, pyrimidine radicals-H), (7.26 m, 2H, Ph-H), 7.36 (s, 1H, Ph-H), 7.42 (m, 1H, Ph-H), 8.43 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 9.12 (sbr, 1H, Ph-H).

MS(ESI ⁺)m/z 426.46[M+H] ⁺(C ₂₂H ₂₇N ₅O ₂S theoretical value 425.55).

C, C, C-three fluoro-N-{3-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-Methanesulfomide [82].

(3-amino methyl-phenyl)-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-base]-amine is processed with three fluoro-mesyl chlorides. Yellow solid.

Analyze RP-HPLC:t_R=11.6 minutes (0-60%MeCN, purity～90%).

¹H-NMR(CD ₃OD)δ：2.53(s，3H，CH ₃)，2.97(s，3H，CH ₃)，4.39(s，2H，CH ₂), 6.94 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 7.01 (d, 1H, J=7.5Hz, Ph-H), 7.31 (d, 1H, J=8.0Hz, Ph-H), 7.60 (d, 1H, J=7.5Hz, Ph-H), 7.67 (s, 1H, Ph-H), 8.28 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

MS(ESI ⁺)m/z 459.33[M+H] ⁺(C ₁₇H ₁₇F ₃N ₆O ₂S theoretical value 458.48).

N-{3-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-Methanesulfomide [83].

(3-amino methyl-phenyl)-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-base]-amine is processed with mesyl chloride. Yellow solid.

Analyze RP-HPLC:t_R=12.8 minutes (0-60%MeCN, purity＞95%).

¹H-NMR(CD ₃OD)δ：2.53(s，3H，CH ₃)，2.88(s，3H，CH ₃)，2.98(s，3H，CH ₃)， 4.28(s，2H，CH ₂), 6.94 (d, 1H, J=5.5Hz, pyrimidine radicals-H), (7.02 d, 1H, J=7.5Hz, Ph-H), 7.29 (t, 1H, J=8.0Hz, Ph-H), 7.52 (d, 1H, J=8.0Hz, Ph-H), 7.90 (s, 1H, Ph-H), 7.98 (s, 1H, NH), 8.28 (d, 1H, J=5.5Hz, pyrimidine radicals-H).

[4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(3-mesyl-phenyl)-amine [84].

By condensation N '-[5-(3-dimethylamino-acryloyl group)-4-methyl-thiazole-2-yl]-N, N-dimethyl-carbonamidine and N-(3-mesyl-phenyl)-guanidine nitrate. Yellow solid.

Analyze RP-HPLC:t_R=13.1 minutes (0-60%MeCN, purity＞97%).

¹H-NMR(DMSO-d ₆)δ：2.55(s，3H，CH ₃)，3.19(s，3H，CH ₃), 6.97 (d, 1H, J=5.5Hz, pyrimidine radicals-H), (7.47 m, 1H, Ph-H), 7.54 (t, 1H, J=7.5Hz, Ph-H), 8.08 (m, 1H, Ph-H), 8.34 (brs, 1H, Ph-H), 8.40 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 9.86 (sbr, 2H, NH₂)。

[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-mesyl-phenyl)-amine [85].

By condensation 3-dimethylamino-1-(2,4-dimethyl-thiazole-5-yl)-propenone and N-(4-mesyl-phenyl)-guanidine nitrate. Yellow solid.

Analyze RP-HPLC:t_R=16.6 minutes (0-60%MeCN, purity＞97%).

¹H-NMR(DMSO-d ₆)δ：2.65(s，3H，CH ₃)，2.66(s，3H，CH ₃)，3.15(s，3H， CH ₃), 7.22 (d, 1H, J=5.5Hz, pyrimidine radicals-H), and 7.84 (d, 2H, J=9.0Hz, Ph-H), 8.03 (d, 2H, J=9.0Hz, Ph-H), 8.61 (d, 1H, J=5.5Hz, pyrimidine radicals-H), 10.23 (sbr, 1H, NH). MS (ESI⁺)m/z 361.17[M+H] ⁺(C ₁₆H ₁₆N ₄O ₂S ₂Theoretical value 361.46).

3,4-dimethyl-5-[2-(4-morpholine-4-base-phenyl amino)-pyrimidine-4-yl]-3H-thiazole-2-ketone [92].

Ammonium methyl N-methyl sulfo--carbaminate (13.1g, 0.105mol; According to method Y.Gelernt etc. 1974, J.Chem.Soc.Perkin Trans.1,2610 are prepared from methyl amine and carbon disulfide) partly be dissolved among the MeOH (150mL). Drip 3-chloro-pentane-2 under the room temperature, 4-diketone (14.9mL, 0.125mol), gradually heat release to 40 ℃. Room temperature stirred after 1 hour, vacuum evaporating solvent. With residue H₂O (50mL) processes and uses CH₂Cl ₂(3 * 50mL) extractions. To merge the organic fraction washing in ground (salt solution), dry (Na₂SO ₄), filter and vacuum evaporation obtains amber grease. With it through chromatogram purifying (300 g SiO₂, with 1: 1 heptane/Et₂The O wash-out obtains the adduct of not cyclisation, then uses Et₂The O wash-out obtains 5-acetyl group-3,4-dimethyl-3H-thiazole-2-ketone, and recrystallization obtains colourless acicular crystal (14.2g) from EtOH.

¹H-NMR(CDCl ₃)δ：2.34(s，3H)，2.59(s，3H)，3.33(s，3H)。

IR (ATR): 1655 and 1621cm^-1(CO str)。

With 5-acetyl group-3,4-dimethyl-3H-thiazole-2-ketone (4.64g, 27.10mmol) and dimethylformamide dimethyl acetal (8.4mL, 59.62mmol) be mixed 100 ℃ of heating 3 hours that are incorporated in flask drying, that filled argon gas. With the mixture cooling, produce some precipitations, add isopyknic Et₂The O postprecipitation increases. Filter the orange solids that forms and use Et₂The O washing obtains the 5-(3-dimethylamino-acryloyl group)-3 of 2.73g, 4-dimethyl-3H-thiazole-2-ketone.

¹H-NMR(d ₆-DMSO)δ：2.52(s，3H)，2.82(bs，3H)，3.11(bs，3H)，3.22(s，3H)， 5.10(d，1H，J＝12.2Hz)，7.61(d，1H，J＝11.7Hz)。

IR (ATR): 1669 and 1630cm^-1(CO str)。

5-(3-dimethylamino-acryloyl group)-3, the condensation between 4-dimethyl-3H-thiazole-2-ketone and N-(4-morpholine-4-base-phenyl)-guanidine nitrate obtains title compound.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=17.5 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞95%).

¹H-NMR(DMSO-d ₆)δ：2.48(3H，s，CH ₃)，3.03(4H，m，2x morph-NCH ₂)， 3.08(3H，s，CH ₃)，3.72(4H，m，2x morph-OCH ₂), 6.85 (1H, d, J=5.2, pyrim-H), 6.89 (2H, d, J=9.2,2x ArH), 7.57 (2H, d, J=9.2,2x ArH), 8.36 (1H, d, J=5.2, pyrimidine-H) and 9.35 (1H, s, NH).

MS(ESI ⁺)m/z 384[M+H] ⁺(C ₁₉H ₂₁N ₅O ₂S theoretical value 383.5).

3,4-dimethyl-5-{2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-pyrimidine-4-yl }-3H-thiazole-2-ketone [93].

This compound utilizes 5-(3-dimethylamino-acryloyl group)-3,4-dimethyl-3H-thiazole-2-ketone and N-[4-(4-methyl-piperazine-1-yl)-phenyl]-condensation reaction between the guanidine nitrate prepares. Linen solid.

Analyze RP-HPLC:t_R(0-60%MeCN was at 0.1%aq CF in=10.9 minutes₃Eluant solution among the COOH 20 minutes, 1mL/ minute, purity＞97%).

¹H-NMR(CDCl ₃)δ：2.42(m，4H，CH ₂)，2.53(s，3H，CH ₃)，3.04(m，4H，CH ₂)， 3.28(s，3H，CH ₃), 6.84 (d, 1H, J=5.5Hz, pyrimidine radicals-H), and 6.86 (d, 2H, J=9.0Hz, Ph-H), 7.54 (d, 2H, J=9.0Hz, Ph-H), 8.35 (d, 1H, J=5.5Hz, pyrimidine radicals-H), and 9.33 (s, 1H, NH).

Embodiment 3

Kinases is analyzed

The compound of investigating above-described embodiment 2 suppresses the ability of multiple protein kinase enzymatic activity. Mixing of suitable peptide substrate realized from the radioactivity phosphoric acid of ATP by measuring. Preparation or obtain recombinant protein kinases and kinase complex by commercial approach. Analysis and utilization 96-orifice plate and suitable analysis buffer (are generally 25mM β-phosphoglycerol, 20mM MOPS, 5mM EGTA, 1mM DTT, 1 mM Na₃VO ₃, pH 7.4) carry out, to wherein adding 2-4 μ g organized enzyme and suitable substrate. By adding Mg/ATP mixture (15mM MgCl₂+ 100 μ M ATP and 30-50kBq/ hole [γ-³²P]-ATP) startup is reacted and mixture is hatched under 30 ℃ as required. To react stopping on ice, then filter p81 filter plate or GF/C filter plate (Whatman Polyfiltronics, Kent, UK). After 75mM positive acid solution washing 3 times, plate is dry, the radioactivity that adds scintillator and mix in the upper measurement of scintillation counter (TopCount, Packard Instruments, Pangbourne, Berks, UK). The compound that is used for the kinases analysis is mixed with the DMSO storage liquid of 10mM and is diluted to the solution of 10%DMSO with analysis buffer. Utilize curve fitting software (GraphPad Prism version 3.00 for Windows, GraphPad Software, San Diego California USA) to analyze data to determine IC₅₀Value (50% ground suppresses the concentration of the test compounds of kinase activity).

CDK7 and 9 analyzes

CTD peptide substrate (biotinyl-Ahx-(Tyr-Ser-Pro-Thr-Ser-Pro-Ser)₄-NH ₂ 1-2 mg/mL) and restructuring people CDK7/ cyclin H, CDK9/ cyclin T1 or CDK9/ cyclin K (0.5-2 μ g) in the presence of the test compounds of difference amount at 20mM MOPS pH 7.2,25mM β-phosphoglycerol, 5mM EGTA, 1mM DTT, the 1mM sodium vanadate, 15 mM MgCl₂With 100M ATP (comprise the trace³²P γ ATP) hatched 45 minutes at 30 ℃ in the microtiter plate of 96-hole with cumulative volume 25 μ L. Reaction is placed on 2 minutes cessation reactions on ice. In each hole, add Avidin (50 μ g), and plate was hatched 30 minutes in room temperature. Sample is transferred on the P81 filter plate of 96-hole, and with 75mM phosphoric acid washing (4 * 200 μ L/ hole). In each hole, add Microscint 40 liquid scintillators (50 μ L), and measure in each sample with Packard Topcount micro plate scintillation counter³²The incorporation of p.

The analysis of Aurora-A (people) kinases

By measurement radioactivity phosphoric acid from ATP under the kinase whose phosphorylation of the aurora-A that commerce obtains mixing of Kemptide substrate (LRRASLG) realized. Analysis and utilization 96-orifice plate and suitable analysis buffer (pH 7.0 for 8mM MOPS, 0.2mM EDTA) are carried out, to wherein adding 5-10ng organized enzyme and 200 μ M substrates (Kemptide). Adding Mg/ATP mixture (10mM magnesium acetate+15 μ M ATP and 30-50kBq/ hole [γ-³³P]-ATP) startup is reacted, and mixture was hatched 40 minutes in room temperature. Add 3% phosphoric acid cessation reaction, then filter p81 filter plate (Whatman Polyfiltronics, Kent, UK). With 75mM positive acid solution washing 5 times and with after the methanol wash 1 time, drying plate adds scintillator, and at the upper radioactivity that mixes of measuring of scintillation counter (TopCount, Packard Instruments, Pangbourne, Berks, UK). The compound that is used for the kinases analysis is mixed with the DMSO storage liquid of 10mM and is diluted to the solution of 10%DMSO with analysis buffer. Utilize curve fitting software (XLfit version 2.0.9, IDBS, Guildford, Surrey, UK) to analyze data to determine IC₅₀Value (50% suppresses the concentration of the test compounds of kinase activity).

The result is summarised in the table 2, and is presented in the table 3 for the selective research approach of more deep kinases of selecting compound.

Embodiment 4

The MTT cytotoxicity analysis

The compound of embodiment 2 is carried out the cell proliferation analysis of standard, utilization is from ATCC (American Type Culture Collection, 10801 University Boulevard, Manessas, VA 20110-2209, USA) human tumor cell line that obtains. Carry out 72-hour MTT (tetrazolium bromide of standard; 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyl Thiazolyl blue tetrazolium bromide compound) analysis (Haselsberger, K.; Peterson, D.C.; Thomas, D.G.; Darling, J.L.Anti Cancer Drugs 1996,7,331-8; Loveland, B.E.; Johns, T.G.; Mack ay, I.R.; Vaillant, F.; Wang, Z.X.; Hertzog, P.J.Biochemistry International 1992,27,501-10). In brief: cell is inoculated on the 96-orifice plate and 37 ℃ of cultivations according to the doubling time spends the night. Test compounds is mixed with DMSO solution and is mixed with 100 μ L cell culture medium solution with 1/3 serial dilution, be added in the cell (in triplicate) and at 37 ℃ and cultivated 72 hours. MTT is prepared into storage liquid and the filtration sterilization of 5mg/mL in cell culture medium. Removing culture medium from cell then washs with 200 μ L PBS. Then MTT solution was cultivated 4 hours with the adding of 20 μ L/ holes and 37 ℃ of lucifuges. Shift out MTT solution and cell is washed with 200 μ L PBS again. Under vibration, the DMSO of MTT dyestuff with 200 μ L/ holes dissolved. Read absorbance at the 540nm place and utilize curve fitting software (GraphPad Prism version 3.00 for Windows, GraphPad Software, San Diego California USA) to carry out data analysis to measure IC₅₀Value (concentration that suppresses the test compounds of 50% Growth of Cells). The result is summarised in the table 4 and selects the more extensive data of compound to be presented in the table 5.

Embodiment 5

In Freshman PBMCs, carry out the HIV-resistant activity evaluation

Utilize clinical paediatrics HIV strain RoJo or WeJo, test representational the compounds of this invention antiviral activity to HIV-1 in human peripheral blood mononuclear cell (PBMCs). PBMCs is cultivated under the condition that the promotion cell is survived and HIV copies. Measure 6-9 log₁₀The DMSO of 100 μ M compounds of serial dilution stores the antiviral activity of solution. Obtain following parameter: IC₅₀And IC₉₀(difference 50 and 90% suppresses the concentration of ground virus replication, TC₅₀(reducing the concentration of cell survival 50%) and TI (therapeutic index: TC₅₀/IC ₅₀)。

HIV and HBV are seronegative fresh PBMCs, separate obtaining from the donations blood (Interstate Blood Bank, Inc.Memphis, TN) that screens. By low-speed centrifugal and be resuspended among the PBS cell precipitation/washing 2-3 time with except the blood platelet that depollutes. To remove leukocytic blood then use Dulbecco's phosphate buffer (DPBS) to dilute and join Lymphocyte Separation Medium (LSM in the 50mL centrifuge tube; Cellgro_, Mediatech, Inc.; Density 1.078 ± 0.002g/mL; Cat.#85-072-CL) upper and then centrifugal. Sucking-off becomes the PBMCs of band from the contact-making surface that forms lightly, and washs with PBS under low-speed centrifugal subsequently. After the final washing, cell is repelled counting by trypan blue, and be resuspended among the RPMI 1640 of additional hyclone (FBS) and Pidolidone, phytolectin (PHA-P, Sigma). With cell 37 ℃ of cultivations. After the cultivation, centrifugal PBMCs, and be resuspended among the RPMI 1640 that is added with FBS, Pidolidone, penicillin, streptomysin, gentamicin and recombinant human il-2 (R﹠D Systems, Inc). Comprise that in culture medium IL-2 is to keep the cell division that is started by the mitogenetic stimulation of PHA. PBMCs is remained on wherein, and two weeks were changed a subculture, until be used for analytical procedure. Cell is cultivated maximum two weeks, in case think and too always be unsuitable for just abandoning for analyzing. Owing to be attached to and organize blake bottle, monocyte exhausts from cultivate.

Analyze for the PBMC of standard, converge the cell that the PHA-P of at least two normal donors stimulates, in the hole, inside of dilution and bed board microtiter plate at the bottom of the 96-hole circle. Be used for minimizing differences between the different donations individualities from the monocyte that obtains more than a donor enrichment, the latter be derived from that HIV infects and elementary lymphocyte population to the quantitative and qualitative difference of the overall response of PHA and IL-2. Each plate comprises Virus/cells control wells (cell adds virus), experimental port (medicine adds cell and adds virus) and compound control wells (medicine adds acellular culture medium, is necessary for MTS monitoring cytotoxicity). Because HIV-1 is to PBMCs and Yan Buhui causes cytopathy, this just allows and uses same analysis plates to carry out antiviral activity and cytotoxicity is measured. In microburet, carry out the dilution of testing drug, and the form of the standard of use is placed on each concentration in the suitable hole. The predetermined dilution of viral storage liquid is placed on each instrument connection (final MOIO.1) in. After the infection, the PBMC culture is at 37 ℃, 5%CO₂Lower maintenance 7 days. Afterwards, collect acellular supernatant sample and be used for analyzing reverse transcriptase activity and/or HIV p24 content. After taking out the supernatant sample, MTS is added in the plate measures cytotoxicity to measure cell viablity compound. By each hole of microexamination and record any unusual.

Reverse transcriptase activity analysis: utilize reverse transcriptase (RT) reaction (Buckheit etc., AIDS Research and human Retroviruses 7:295-302,1991) based on microtiter plate. The triphosphoric acid thymidine in tritium generation (³H-TTP, 80Ci/mmol, NEN) with 1: 1 dH₂O: the solution of ethanol and activity are that 1mCi/mL accepts. Poly-rA: few dT template: primer (Pharmacia) is prepared into storage solutions, then packing and frozen at-20 ℃. The fresh preparation on the basis of using every day of RT reaction buffer. Prepare final reactant mixture: by mixing³H-TTP、dH ₂O, poly-rA: liquid during few dT storage liquid and reaction are slow. Be placed on this reactant mixture in the round bottom microtiter plate and add the supernatant that contains virus and also mix. Plate was cultivated 60 minutes at 37 ℃. After the cultivation, with the reaction volume specking to the DE81 filter-mats (Wallac) in sodium phosphate buffer or 2 * SSC (Life Technologies). Then, at distilled water, in 70% ethanol, wash, then dry. Utilize the radioactivity that the liquid sudden strain of a muscle technology of standard quantitatively mixes (count per minute, CPM). The compounds of this invention result who selects is presented in the following table 6.

Do not departing under the scope and spirit situation of the present invention, the various modifications of the aspect of the present invention of description and variant are apparent for those of ordinary skill in the art. Although the present invention is described in conjunction with concrete preferred embodiment, is construed as claimed the present invention and should exceedingly be restricted to described specific embodiment. In fact, the obvious enforcement of those of ordinary skill in the related art multiple modification of the present invention all is included within the scope of following claim.

Table 1. embodiment compound

Table 2. embodiment compound (referring to

Table 1)

Inhibitory action to protein kinase

Numbering	Kinase inhibition IC₅₀(μM)
Numbering	Kinase inhibition IC₅₀(μM)										CDK1 cyclin B¹	CDK2 cyclin A¹	CDK2 cyclin E¹	CDK4 cyclin D1¹	CDK7 cyclin H¹	CDK9 cyclin T1¹	GSK-3β ¹	PLK-1 ¹	ARK-2
1	17	0.70	0.81	2.4	30	2.7	＞100	98	0.011		CDK1 cyclin B¹	CDK2 cyclin A¹	CDK2 cyclin E¹	CDK4 cyclin D1¹	CDK7 cyclin H¹	CDK9 cyclin T1¹	GSK-3β ¹	PLK-1 ¹	ARK-2
1	17	0.70	0.81	2.4	30	2.7	＞100	98	0.011	2	75	2.2	3.9	3.9	97	23	＞100	＞100
3	71	4.7	0.43	1.4	106	12	＞100	＞150		2	75	2.2	3.9	3.9	97	23	＞100	＞100
3	71	4.7	0.43	1.4	106	12	＞100	＞150		4	30	1.1	0.90	0.43	12	1.8	＞100	＞100
5	5.6	1.1	0.87	1.7	5.6	6.1	21	35		4	30	1.1	0.90	0.43	12	1.8	＞100	＞100
5	5.6	1.1	0.87	1.7	5.6	6.1	21	35		6	3.0	0.85	0.71	0.39	1.3	1.0	5.2	13
7	4.2	1.3	1.8	0.62	2.2					6	3.0	0.85	0.71	0.39	1.3	1.0	5.2	13
7	4.2	1.3	1.8	0.62	2.2					8	4.9	1.1	1.2	0.36	0.97	0.51	39	＞150
9	5.2	1.2	2.2	0.43	1.3	0.21				8	4.9	1.1	1.2	0.36	0.97	0.51	39	＞150
9	5.2	1.2	2.2	0.43	1.3	0.21				10	51	4.4	15	11
11	2.4	2.2	0.26	0.0098	0.019	1.1	6.0	19		10	51	4.4	15	11
11	2.4	2.2	0.26	0.0098	0.019	1.1	6.0	19		12	4.2	1.0	1.8	0.19	1.1	0.28	53	55
13	5.6	0.57	0.28	0.67	0.37	0.042				12	4.2	1.0	1.8	0.19	1.1	0.28	53	55
13	5.6	0.57	0.28	0.67	0.37	0.042				14			0.068	2.2		0.34
15	5.4	0.85	0.13	2.0	0.34	0.070	0.61	＞150		14			0.068	2.2		0.34
15	5.4	0.85	0.13	2.0	0.34	0.070	0.61	＞150		16	2.8	0.65	0.32	6.7	1.1	0.11	0.68	＞150	2.8
17	2.0		0.21							16	2.8	0.65	0.32	6.7	1.1	0.11	0.68	＞150	2.8
17	2.0		0.21							18			0.18	1.1		0.53
20	1.9	0.52	0.076	0.77		0.037				18			0.18	1.1		0.53
20	1.9	0.52	0.076	0.77		0.037				21	0.54	0.32	0.097	1.3	4.9	0.46	14	＞200
22	0.24	0.098	0.0025	1.7	0.20	0.11	0.25	＞100		21	0.54	0.32	0.097	1.3	4.9	0.46	14	＞200
22	0.24	0.098	0.0025	1.7	0.20	0.11	0.25	＞100		23	3.1	1.4	0.19	3.0	0.81	0.40	1.2	24
24			1.1	0.44		0.0058				23	3.1	1.4	0.19	3.0	0.81	0.40	1.2	24
24			1.1	0.44		0.0058				25	9.4	3.0	0.22	0.97	3.2	0.68	0.083
28	36	12	2.6	29						25	9.4	3.0	0.22	0.97	3.2	0.68	0.083
28	36	12	2.6	29						29	0.86	0.49	0.47	1.1	1.2		0.56
31			0.30	5.6						29	0.86	0.49	0.47	1.1	1.2		0.56
31			0.30	5.6						32			0.005	1.1		0.0014	0.21
33			0.23	0.68						32			0.005	1.1		0.0014	0.21
33			0.23	0.68						34			1.4	7.0			0.73
35	15	3.0	0.80	4.7		1.8				34			1.4	7.0			0.73

36	33	13	3.4	8.8	4.0	4.8
36	33	13	3.4	8.8	4.0	4.8			37	＞100	16	8.0	18		6.3
38	1.9	0.58	2.7	1.8		1.1			37	＞100	16	8.0	18		6.3
38	1.9	0.58	2.7	1.8		1.1			39	11	2.7	1.2	32		15
40	61	14	64	7.4		8.9			39	11	2.7	1.2	32		15
40	61	14	64	7.4		8.9			45	2.5	0.84	0.66	0.37	17	0.24
48	12	1.7	2.1	2.6	3.5				45	2.5	0.84	0.66	0.37	17	0.24
48	12	1.7	2.1	2.6	3.5				50	3.4	0.89	0.39	0.95	13	0.0018
51	11	2.9	1.7	0.40	9.6				50	3.4	0.89	0.39	0.95	13	0.0018
51	11	2.9	1.7	0.40	9.6				52	2.5	1.3	0.44	0.18	2.0
53	5.2	5.3	0.52	0.040	0.44	0.093	23		52	2.5	1.3	0.44	0.18	2.0
53	5.2	5.3	0.52	0.040	0.44	0.093	23		54	13	57	0.098	0.032	2.1	0.11	19
55	2.4	61	0.079	1.0	2.2	2.1	67		54	13	57	0.098	0.032	2.1	0.11	19
55	2.4	61	0.079	1.0	2.2	2.1	67		56	18	68	0.60	0.022	0.85	17	＞100
57	7.7	73	0.35	0.071	0.19	12	74		56	18	68	0.60	0.022	0.85	17	＞100
57	7.7	73	0.35	0.071	0.19	12	74		59	0.71	0.11	0.14	0.086	2.6	0.47	2.2
61	2.5	2.8	0.60	0.042	2.3	1.5	6.8		59	0.71	0.11	0.14	0.086	2.6	0.47	2.2
61	2.5	2.8	0.60	0.042	2.3	1.5	6.8		62	0.98	1.5	0.21	0.0070	0.041	0.098	4.7
63	48	12	1.7	7.7	20	2.7	8.8	46	62	0.98	1.5	0.21	0.0070	0.041	0.098	4.7
63	48	12	1.7	7.7	20	2.7	8.8	46	64	0.74	0.31	0.080	0.13	0.59	0.10	2.1	18
65			0.33	0.11				＞100	64	0.74	0.31	0.080	0.13	0.59	0.10	2.1	18
65			0.33	0.11				＞100	66	0.12	0.10	0.11	0.63	2.1
67			0.42	0.24				＞100	66	0.12	0.10	0.11	0.63	2.1
67			0.42	0.24				＞100	68	0.15	0.061	0.065	0.042	0.48		0.82
71	0.33	0.0060	0.22		2.4	4.2	2.4		68	0.15	0.061	0.065	0.042	0.48		0.82
71	0.33	0.0060	0.22		2.4	4.2	2.4		72	62	12	0.73	25	9.6	4.1	48
73	1.7	1.3	1.0	0.23	2.0	0.55	5.2		72	62	12	0.73	25	9.6	4.1	48
73	1.7	1.3	1.0	0.23	2.0	0.55	5.2		76	1.8	0.14	0.15	3.2	11		5.4
77	72	1.0	0.15	3.4	1.0	0.26	6.1		76	1.8	0.14	0.15	3.2	11		5.4
77	72	1.0	0.15	3.4	1.0	0.26	6.1		82	2.7	1.3	0.014	2.3	4.0		1.2
83	0.48	0.15	0.025	0.67	0.37		1.0		82	2.7	1.3	0.014	2.3	4.0		1.2
83	0.48	0.15	0.025	0.67	0.37		1.0		84	0.14	0.05	0.076	0.3	0.43		0.30
85	0.048	0.001	0.028	3.8	11				84	0.14	0.05	0.076	0.3	0.43		0.30
85	0.048	0.001	0.028	3.8	11				91	0.12	0.10	0.11	0.63
92	15	1.2	0.64	1.3	2.8		0.47		91	0.12	0.10	0.11	0.63
92	15	1.2	0.64	1.3	2.8		0.47		93	4.4	1.1	0.84	0.51	0.36	0.3	0.43

¹, abbreviation is explained referring to table 3;², ARK-2:aurora kinases-2 (known also is aurora A kinases).

Table 3. is selected the kinases specificity (IC of compound₅₀，μM)

Kinases	Compound
	Compound					1	3	11	15	16
	CDK2/E ¹ CDK2/A ² CDK1/B1 ³ CDK4/D1 ⁴ CDK7/H ⁵ CDK9/T1 ⁶ ERK2 ⁷ p70/S6 ⁸ CK2 ⁹ PKCα ¹⁰ Akt/PKB ¹¹ PKA ¹² SAPK2a ¹³ PLK1 ¹⁴ CaMKII ¹⁵ Ab1 ¹⁶ GSK-3 ¹⁷	0.48 0.44 21 2.2 56 2.3 ＞100 2.3 ＞100 ＞100 ＞100 5.8 ＞100 ＞100 26 ＞100 ＞100	0.68 0.44 ＞100 0.15 ＞100 8.5 ＞100 2.6 ＞100 ＞100 ＞100 39 ＞100 ＞100 ＞100 50 ＞100	0.26 2.2 2.4 0.0098 0.019 1.1 ＞100 ＞100 ＞100 ＞100 ＞100 11 ＞100 19 56 72 6.0	0.15 0.40 1.6 1.6 0.39 0.11 ＞100 ＞100 ＞100 ＞100 ＞100 2.0 ＞100 ＞100 3.9 0.76 0.54	1	3	11	15	16	0.35 0.65 2.8 6.7 0.97 0.20 ＞100 8.0 ＞100 53 ＞100 4.9 ＞100 ＞100 11 1.5 0.68

¹, CDK2/ cyclin E compound;², CDK2/ cyclin A compound;³, CDK1/ cyclin B1 compound;

⁴, CDK4/ cyclin D1 compound;⁵, CDK7/ cyclin H/MAT 1 compound;⁶, CDK9/ cyclin T1 compound;⁷, extracellular-signal-regulated kinases 2;⁸, p70 ribosomal protein S6K;⁹, casein kinase 2;¹⁰, protein kinase C α;¹¹, protein kinase B;¹², the cAMP-deopendent protein kinase;¹³, stress-activated protein kinase 2a;¹⁴, polo-sample kinases 1;¹⁵, calmodulin-dependence kinases II;¹⁶, the Ableson EGFR-TK;¹⁷, glycogen synthase kinase 3 β.

Table 4. act on people's cancer cell system anti-proliferative activity (referring to)

Numbering	72-hour MTT IC₅₀(μM)
	72-hour MTT IC₅₀(μM)			A549	HT29	Saos-2
	1	2.1	1.7	A549	HT29	Saos-2	1.9
2	1	2.1	1.7	3.5	3.3	4.8	1.9
2	3	3.7	2.8	3.5	3.3	4.8	3.1
4	3	3.7	2.8	0.77	0.92	1.2	3.1
4	5	3.8	2.2	0.77	0.92	1.2	3.9
6	5	3.8	2.2	1.3	1.1	0.78	3.9
6	7	3.9	1.6	1.3	1.1	0.78	1.6
8	7	3.9	1.6	0.61	0.80	0.38	1.6
8	9	3.0	2.0	0.61	0.80	0.38	2.0
10	9	3.0	2.0	11	6.4		2.0
10	11	2.2	1.6	11	6.4		3.6
12	11	2.2	1.6	0.71	0.74	0.43	3.6
12	13	3.1	2.8	0.71	0.74	0.43	1.9
14	13	3.1	2.8	0.99	0.73	1.5	1.9
14	15	1.1	1.0	0.99	0.73	1.5	1.9
16	15	1.1	1.0	0.53	0.29		1.9
16	17	1.1	1.2	0.53	0.29		1.2
18	17	1.1	1.2	2.5	2.4	1.1	1.2
18	20	5.8	6.3	2.5	2.4	1.1
21	20	5.8	6.3	8.6	4.1	4.3
21	22	0.81	0.52	8.6	4.1	4.3	0.60
23	22	0.81	0.52	3.8	1.1	4.4	0.60
23	24	0.14	0.14	3.8	1.1	4.4	0.17
25	24	0.14	0.14	0.97	1.3	1.6	0.17
25	28	9.9	6.74	0.97	1.3	1.6	15
29	28	9.9	6.74	0.69	2.6	0.72	15
29	31	2.0	4.1	0.69	2.6	0.72	0.81

32	0.10	0.17	0.16
32	0.10	0.17	0.16	33	0.33	0.11	0.30
34	3.9	3.2	3.3	33	0.33	0.11	0.30
34	3.9	3.2	3.3	35	15	7.7	26
36	26	9.6	38	35	15	7.7	26
36	26	9.6	38	37	35	15	73
38	2.7	1.7	5.3	37	35	15	73
38	2.7	1.7	5.3	39	0.80	0.72	0.95
40	4.4	0.73	4.3	39	0.80	0.72	0.95
40	4.4	0.73	4.3	45	2.6	2.2	2.8
47	2.7	0.35	1.6	45	2.6	2.2	2.8
47	2.7	0.35	1.6	48	3.0	2.6	3.8
50	0.16	0.16	0.16	48	3.0	2.6	3.8
50	0.16	0.16	0.16	51	1.9	1.4	1.1
52	1.6	1.6	1.1	51	1.9	1.4	1.1
52	1.6	1.6	1.1	53	0.77	0.95	0.53
54	2.9	2.7	1.9	53	0.77	0.95	0.53
54	2.9	2.7	1.9	55	2.3	5.1	1.4
56	4.4	2.9	5.0	55	2.3	5.1	1.4
56	4.4	2.9	5.0	57	2.7	0.24	3.8
59	2.4	1.7	1.9	57	2.7	0.24	3.8
59	2.4	1.7	1.9	61	0.72	0.53	1.0
62	0.19	0.18	0.26	61	0.72	0.53	1.0
62	0.19	0.18	0.26	63	0.98	1.4	1.2
64	0.19	0.41	0.34	63	0.98	1.4	1.2
64	0.19	0.41	0.34	65	3.2	4.8	0.65
67	14	14	1.1	65	3.2	4.8	0.65
67	14	14	1.1	71	80	71	10
72	32	20	18	71	80	71	10
72	32	20	18	73	1.5	5.5	2.9
76	5.8	1.8	1.3	73	1.5	5.5	2.9
76	5.8	1.8	1.3	77	0.31	0.21	0.35

In Vitro Anti proliferative activity (72-hour MTT, the IC of the compound that table 5. is selected₅₀，μM)

Clone	Compound
Clone	Compound					Type	Title	1	11	15	16
Uterus, osteosarcoma osteosarcoma mammary gland uterine neck colon colon colon colon sdenocarcinoma of stomach leiomyosarcoma leiomyosarcoma chronic myelogenous leukemia leukaemia progranulocyte leukaemia lung lung neuroblastoma osteogenic sarcoma prostate skin keratin cell uterus	Saos-2 U2OS MCF-7 Hela HT29 Lovo H1299 HCT-116 AGS SKUT-1B SKUT-1 K562 CCRF-CEM HL60 nci-H460 A549 SK-N-MC SJSA-1 DU-145 Hacat Messa Messa-Dx5	0.1 2.1 ＞5 1.8 1.1 0.9 0.9 0.9 1.1 0.9 3.8 0.9 1.8 0.2 1.0 0.3 ＞5 1.5 1.1 0.2 0.2	3.7 2.3 1.9 6.2 1.6 2.0 1.1 0.6 1.3 0.3 0.8 2.1 0.5 1.7 0.7 2.2 0.6 4.3 1.0 1.0 0.1 0.2	0.4 1.02 0.9 0.7 0.5 0.7 1.3 0.6 1.1 0.2 0.9 4.6 2.6 2.2 1.2 0.6 0.5 1.9 1.3 1.5 0.9 0.4	0.6 0.48 0.39 0.4 0.3 0.3 0.6 0.3 0.3 0.1 0.2 2.5 1.1 0.6 0.3 0.5 0.4 1.0 0.6 1.1 0.4 0.1	Type	Title	1	11	15	16
						On average (all transformants)		1.1	1.6	1.2	0.6
SD (all transformants)		0.9	1.4	1.0	0.5	On average (all transformants)		1.1	1.6	1.2	0.6
SD (all transformants)		0.9	1.4	1.0	0.5	Average (all transformants)		1.0	1.1	0.9	0.4
Human foreskin fibroblasts (unconverted) fetal lung fibroblast (unconverted) fetal lung fibroblast (unconverted)	Hs27 IMR-90 WI38	＞5 ＞5 ＞5	19 31 22	1.7 2.5 ＞5	＞5 1.7 1.4	Average (all transformants)		1.0	1.1	0.9	0.4

Table 6. anti-HIV is active to be summed up

Compound	HIV-1/PBMC		PBMC TC ₅₀(μM)	TI
	HIV-1/PBMC				IC ₅₀(nM)	IC ₉₀(nM)
	AZT ^a	4			IC ₅₀(nM)	IC ₉₀(nM)	10	＞1	＞231
1	AZT ^a	4	1,327	2,645	6.1	4.6	10	＞1	＞231
1	3	297	1,327	2,645	6.1	4.6	679	＞100	＞337
4	3	297	166	295	9.4	57	679	＞100	＞337
4	15	124	166	295	9.4	57	385	2.4	20
53	15	124	812	871	1.6	1.9	385	2.4	20

^a, AZT: Zidovudine; The inverase that uses clinically is as positive control.

Claims

1. formula I compound or pharmaceutically acceptable salt thereof,

Wherein:

(A)X ¹And X²One of be S, and X¹And X²In another is N;

" a " is singly-bound; And

R ²Independently together as following to R¹、R ^3-8Definition; Or

(B)X ¹And X²One of be S, and X¹And X²In another is NR¹⁷；

" a " and " d " respectively is two keys; And

" b ", " c ", " e " and " f " respectively are singly-bound;

R ²Be oxo group; And

R ¹⁷Be H or alkyl;

Wherein:

(i)-single-, two-or polyhydroxylated alicyclic group;

-two-or polyhydroxylated aliphatic or aromatic group;

-carbohydrate derivative;

-aliphatic or aromatic group comprise acid amides, sulfoxide, sulfone or sulfonamide functional group; Or

-halogenated alkyl carbonyl;

(ii)COOH、SO ₃H、OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

-SO ₂-alkyl;

-alkyl, optional by one or more OH group replacement;

-CO-alkyl;

-aralkyl;

-COO-alkyl; And

-ether, optional by one or more OH group replacement; And

Wherein Y is not pyridine radicals;

(iv) natural or non-natural amino acid, peptide or peptide derivative;

(v)OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

(vi) Y as defined above, but be not guanidine and quaternary amine;

(viii)(CH ₂) _nNR ¹⁴COR ¹²、(CH ₂) _n’NR ¹⁵SO ₂R ¹³Or SO₂R ¹⁶, R wherein¹²、R ¹³And R¹⁶Respectively doing for oneself to choose wantonly comprises one or more heteroatomic alkyl, and it is optional by one or more OH, NH of being selected from₂, halogen and NO₂Substituting group replace R¹⁴And R¹⁵Be H or alkyl independently of one another, and n and n ' are 0,1,2 or 3 independently of one another;

(x)(CH ₂) _rNH ₂ Wherein r is 0,1,2 or 3;

(xi)(CH ₂) _r’OH; Wherein r ' is 0,1,2 or 3;

Condition is that described compound is not:

3-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-methyl alcohol;

2-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-ethanol.

2. according to claim 1 formula Ib compound or pharmaceutically acceptable salt thereof,

X wherein¹And X²One of be S, and X¹And X²In another be N, and Z, R^1-8Such as definition in the claim 1.

3. the compound of claim 2, wherein X¹Be S and X²Be N.

4. each compound in the aforementioned claim, wherein Z is NH.

5. each compound, wherein R in the aforementioned claim³Be H.

6. each compound, wherein R in the aforementioned claim²、R ⁵、R ⁶Or R⁷In at least one for containing R⁹Or R¹⁰Group or be R¹¹。

7. each compound, wherein X in the aforementioned claim¹Be S, X²Be N, Z is NH, R¹Be Me, R²Be alkyl or amino, R³Be H, R⁵、R ⁶And R⁷In one or two be CF₃, OH, O-alkyl, halogen, NO₂、NH ₂, NH-alkyl or N-(alkyl)₂, and R²、R ⁵、R ⁶Or R⁷In at least one for containing R⁹Or R¹⁰Group or be R¹¹。

8. each compound, wherein R in the claim 1～5¹、R ²、R ³、R ⁴、R ⁵、R ⁶、 R ⁷And R⁸In at least one is R¹¹。

9. each compound in the aforementioned claim, wherein said solubilizing group is R¹¹, and R¹¹For:

(a) Y as defined in claim 1, but get rid of guanidine, wherein Y also can be and comprises one or more=alicyclic, fragrance or the heterocyclic radical of N-group;

10. the compound of claim 9, wherein Y is for comprising functional group-O-, NH₂,-NH-,=one or more alicyclic group in N-, quaternary amine or the amidine, and wherein Y is optional is replaced by one or more substituting groups such as the definition in the claim 1.

11. each compound in the aforementioned claim, wherein Y is morpholine or piperazinyl, and each group is optional by one or more SO that are selected from₂-alkyl, optional alkyl, CO-alkyl, aralkyl, the COO-alkyl that is replaced by one or more OH group, and the optional ether that is replaced by one or more OH group.

12. each compound in the claim 1～9, wherein Y is 2-oxo-six hydrogen-thieno [3,4-d] imidazole radicals.

13. each compound, wherein R in the aforementioned claim²、R ⁶Or R⁷In at least one is R¹¹。

14. each compound, wherein R in the aforementioned claim¹¹Be selected from following group:

15. the compound of claim 13 or 14, wherein R⁶Or R⁷Be R¹¹。

16. the compound of claim 15, wherein R⁶Be R¹¹And R²、R ⁴、R ⁵、R ⁷And R⁸Be selected from independently of one another alkyl, H, CF₃, OH, O-alkyl, halogen, NO₂、NH ₂, NH-alkyl and N-(alkyl)₂。

17. according to claim 15 or 16 compound, wherein R⁶Be R¹¹And R²、R ⁴、R ⁵、 R ⁷And R⁸Be selected from independently of one another alkyl, H, O-alkyl, halogen, NO₂、NH ₂With the NH-alkyl.

18. each compound, wherein R according to claim 15～17⁶Be R¹¹And R⁴、R ⁵、 R ⁷And R⁸All be H and R²Be selected from alkyl, O-alkyl, NH₂With the NH-alkyl.

19. each compound, wherein R according to claim 15～18¹¹Be selected from:

20. compound according to claim 15, wherein R⁷Be R¹¹And R⁴、R ⁵、R ⁶、R ⁸All be H, and R²Be selected from alkyl, O-alkyl, NH₂With the NH-alkyl.

21. compound according to claim 20, wherein R¹¹Be selected from:

22. according to claim 13 or 14 compound, wherein R²Be R¹¹。

23. compound according to claim 22, wherein R²Be R¹¹And R⁴、R ⁵、R ⁶、R ⁷And R⁸Be selected from independently of one another alkyl, H, CF₃, OH, O-alkyl, halogen, NO₂、NH ₂, NH-alkyl and N-(alkyl)₂。

24. according to claim 22 or 23 compound, wherein R²Be R¹¹And R⁴、R ⁵、R ⁶、 R ⁷And R⁸Be selected from independently of one another H, O-alkyl, halogen, N-(alkyl)₂、NO ₂。

25. each compound, wherein R according to claim 22～24²Be R¹¹，R ⁵Or R⁷One of be selected from NO₂, alkoxyl, halogen and N-(alkyl)₂, and R⁴、R ⁵、R ⁶、R ⁷And R⁸In other groups all be H.

26. each compound, wherein R according to claim 22～24¹¹Be selected from:

27. according to each compound in the aforementioned claim, wherein R¹Be methyl, Z is NH and R³Be H.

28. formula Id compound according to claim 1, or its officinal salt,

29. compound according to claim 28, wherein R¹And R^3-8As defining in each among claim 4,9-12, the 14-17,19,21.

30. according to each compound in the aforementioned claim, be selected from following compound: 1 4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine

2 [4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine 3 [4-(2-N-methylamino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholino phenyl)-amine 4 [4-(2-ethyl amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine 5 1-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-ethyl ketone 6 [4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-piperazine-1-base-phenyl)-amine 7 [4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[4-(4 '-2 "-the ethoxy ethanol piperazinyl)-phenyl]-amine 8 3-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-third-1-alcohol 9 2-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-ethanol 10 [4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[4-(4-mesyl-piperazine-1-yl)-phenyl]-amine 11 [4-(4-benzyl-piperazine-1-yl)-phenyl]-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-base]-amine 12 [4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine 13 3-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide 14 (2S)-2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide 15 (2R, 3R)-2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide 16 (2R)-2-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide 17 (2S, 3S)-2-amino-3-hydroxyl-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide 18 4-amino-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-butyramide 19 3-amino-N-{4-methyl-5-[2-(4-morpholine-4-base-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-propionamide 20 3-bromo-N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-propionamide 21 N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-morpholine-4-base-propionamide

22 N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-3-morpholine-4-base-propionamide 23 N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-3-(4-methyl-piperazine-1-yl)-propionamide 24 2-chloro-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-acetamide 25 2-chloro-N-{5-[2-(3-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide 26 2-chloro-N-{5-[2-(3-methoxyl group-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide 27 2-chloro-N-{5-[2-(4-dimethylamino-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide 28 4-(4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-base carbamoyl }-methyl)-piperazine-1-carboxylic acid tert-butyl group ester 29 N-{5-[2-(4-dimethylamino-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-2-[2-(2-hydroxyl-ethyoxyl)-ethyl is amino]-acetamide 30 6-[5-(2-oxo-six hydrogen-thieno [3,4-d] imidazoles-4-yl)-valeryl is amino]-caproic acid (2-{4-methyl-5-[2-(4-morpholine-4-base-phenyl amino)-pyrimidine-4-yl]-thiazole-2-base carbamoyl }-ethyl)-acid amides 31 N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-Methanesulfomide 32 N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-Methanesulfomide 33 2-chloro-N-{5-[2-(4-fluoro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide 34 2-chloro-N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-acetamide 35 N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-morpholine-4-base-propionamide 36 N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-(2-diethylamino-ethyl is amino)-propionamide 37 N-{5-[2-(4-chloro-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-(2-morpholine-4-base-ethyl is amino)-propionamide 38 N-{5-[2-(4-methoxyl group-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-morpholine-4-base-propionamide 39 N-{5-[2-(3-methoxyl group-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-morpholine-4-base-propionamide

40 N-{5-[2-(4-methoxyl group-phenyl amino)-pyrimidine-4-yl]-4-methyl-thiazole-2-yl }-3-(4-methyl-piperazine-1-yl)-propionamide 45 N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-acetamide 48 N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-N-methyl-acetamide 49 1-(4-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-propan-2-ol 50 2-chloro-N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-acetamide 51 N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-2-morpholine-4-base-acetamide 52 N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-2-[1,2,4] triazol-1-yl-acetamide 53 N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-2-pyrrolidin-1-yl-acetamide 54 N-{4-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-2-imidazoles-1-base-acetamide 55 3-[4-(4-methyl-2-morpholine-4-base-thiazole-5-yl)-pyrimidine-2--amino]-phenol 56 [4-(4-methyl-2-morpholine-4-base-thiazole-5-yl)-pyrimidine-2-base]-(4-morpholine-4-base-phenyl)-amine 57 N, N-dimethyl-N '-[4-(4-methyl-2-morpholine-4-base-thiazole-5-yl)-pyrimidine-2-base]-benzene-Isosorbide-5-Nitrae-diamines 59 2-{4-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-ethanol 61 1-(4-{4-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-piperazine-1-yl)-ethyl ketone 62 [4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-base]-(4-piperazine-1-base-phenyl)-amine 63 N-{3-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-acetamide 64 N-{3-[4-(2-ethyl amino-4-methyl-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-acetamide 65 (3-amino methyl-phenyl)-[4-(2-ethyl amino-4-methyl-thiazole-5-yl)-pyrimidine-2-yl]-amine 66 N-{3-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-acetamide 67 (3-amino methyl-phenyl)-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-yl]-amine 68 3-[4-(2-ethyl amino-4-methyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-methyl alcohol

71 [4-(4-methyl-2-morpholine-4-base-thiazole-5-yl)-pyrimidine-2-base]-(3-nitro-phenyl)-amine 72 2-chloro-5-[4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-methyl alcohol 73 2-chloro-5-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-methyl alcohol 76 [4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(4-mesyl-phenyl)-amine 77 [4-(2-methoxyl group-ethyoxyl)-3-nitro-phenyl]-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2-base]-amine 81 [4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-[3-(2-morpholine-4-base-ethoxyl methyl)-phenyl]-amine 82 C, C, C-three fluoro-N-{3-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-Methanesulfomide 83 N-{3-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-benzyl }-Methanesulfomide 84 [4-(2-amino-4-methyl-thiazole-5-yl)-pyrimidine-2-base]-(3-mesyl-phenyl)-amine 85 [4-(2,4-dimethyl-thiazole-5-yl)-pyrimidine-2-base]-(4-mesyl-phenyl)-amine 91 3-[4-(4-methyl-2-methylamino-thiazole-5-yl)-pyrimidine-2--amino]-phenyl }-methyl alcohol 92 3,4-dimethyl-5-[2-(4-morpholine-4-base-phenyl amino)-pyrimidine-4-yl]-3H-thiazole-2-ketone 93 3,4-dimethyl-5-{2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-pyrimidine-4-yl }-3H-thiazole-2-ketone.

31. according to each compound in the aforementioned claim, be selected from following compound: [4], [8], [12], [14], [16], [22], [24], [25], [29], [32], [33], [39], [40], [50], [53], [61], [57], [62], [63], [64], [65] and [77].

32. compound according to claim 31 is selected from following compound: [24], [25], [32], [33], [50], [62] and [64].

33. each compound according to claim 1～30 is selected from following compound: [11], [13], [14], [15], [20], [21], [22], [24], [25], [32], [50], [53], [54], [55], [56], [57], [59], [61], [62], [64], [68], [71], [82], 83], [84] and [85].

34. compound according to claim 33, described compound is selected from following compound: [11], [22], [24], [32], [50], [62], [71] and [85].

35. a pharmaceutical composition, comprise according to claim 1～34 in each compound and pharmaceutically acceptable diluent, excipient or carrier.

36. according to claim 1～26 each compound for the preparation of the treatment proliferative disease medicine in purposes.

37. purposes according to claim 36, wherein said proliferative disease are cancer or leukaemia.

38. according to claim 36 or 37 purposes, other anticancer compound combination medicine-feeding of wherein said compound and one or more.

39. formula Ia compound, or its officinal salt for the preparation of the treatment viral disease medicine in purposes,

Wherein:

(A)X ¹And X²One of be S, and X¹And X²In another is N;

" a " is singly-bound;

" b ", " c ", " d ", " e " and " f ' be single or two keys to form the thiazole basic ring;

R ²Independently together as following to R¹、R ^3-8Definition; Or

(B)X ¹And X²One of be S, and X¹And X²In another is NR¹⁷；

" a " and " d " respectively is two keys;

" b ", " c ", " e " and " f " respectively are singly-bound;

R ²Be oxo group; And

R ¹⁷Be H or alkyl;

Wherein:

R ¹、R ³、R ⁴、R ⁵、R ⁶、R ⁷And R⁸H, alkyl, alkyl-R independently of one another⁹, aryl, aryl-R⁹, aralkyl, aralkyl-R⁹, halogen, NO₂, CN, OH, O-alkyl, COR⁹、COOR ⁹, O-aryl, O-R⁹、NH ₂, NH-alkyl, NH-aryl, N-(alkyl)₂, N-(aryl)₂, N-(alkyl) (aryl), NH-R⁹、N-(R ⁹)(R ¹⁰), N-(alkyl) (R⁹), N-(aryl) (R⁹)、COOH、CONH ₂, CONH-alkyl, CONH-aryl, CON-(alkyl) (R⁹), CON (aryl) (R⁹)、CONH-R ⁹、 CON-(R ⁹)(R ¹⁰)、SO ₃H、SO ₂-alkyl, SO₂-alkyl-R⁹、SO ₂-aryl, SO₂-aryl-R⁹、 SO ₂NH ₂、SO ₂NH-R ⁹、SO ₂N-(R ⁹)(R ¹⁰)、C _F3, CO-alkyl, CO-alkyl-R⁹, CO-aryl, CO-aryl-R⁹Or R¹¹, wherein alkyl, aryl, aralkyl can further be selected from halogen, NO by one or more₂, OH, O-methyl, NH₂、COOH、CONH ₂And CF₃Group replace;

(i)-single-, two-or polyhydroxylated alicyclic group;

-two-or polyhydroxylated aliphatic or aromatic group;

-carbohydrate derivative;

-halogenated alkyl carbonyl;

(ii)COOH、SO ₃H、OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

-SO ₂-alkyl;

-alkyl, optional by one or more OH group replacement;

-CO-alkyl;

-aralkyl;

-COO-alkyl; And

-ether, optional by one or more OH group replacement; And

Wherein Y is not pyridine radicals;

(iv) natural or non-natural amino acid, peptide or peptide derivative;

(v)OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

(vi) Y as defined above, but be not guanidine and quaternary amine;

(x)(CH ₂) _rNH ₂ Wherein r is 0,1,2 or 3;

(xi)(CH ₂) _r’OH; Wherein r ' is 0,1,2 or 3.

40. purposes according to claim 39, each defines in wherein said formula Ia compound such as the claim 2～30.

41. purposes according to claim 39, wherein said formula Ia compound in the claim 30 definition or additionally be selected from following compound:

N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl } Methanesulfomide [32];

2-chloro-N-{4-methyl-5-[2-(3-nitro-phenyl amino)-pyrimidine-4-yl]-thiazole-2-yl }-acetamide [24]; And

42. according to 39～41 each purposes in the claim, the compound of wherein said formula Ia is selected from following compound: [1], [3], [4], [15] and [53].

43. each purposes according to claim 39～42, wherein said viral disease are selected from human cytomegalovirus (HCMV), herpes simplex types 1 virus (HSV-1), I type human immunodeficiency virus (HIV-1) and varicella virus (VZV).

44. each compound is used for the kinase whose purposes of CKIs in the claim 1～34.

45. purposes according to claim 44, wherein said protein kinase are cyclin dependence kinases.

46. purposes according to claim 45, wherein said protein dependent kinase is selected from CDK2, CDK7, CDK8 and CDK9.

47. a treatment proliferative disease method, described method comprise to administration treatment effective dose according to claim 1～34 in each compound.

48. a method for the treatment of viral disease, described method comprise the formula Ia compound or pharmaceutically acceptable salt thereof to administration treatment effective dose,

Wherein:

(A)X ¹And X²One of be S, and X¹And X²In another is N;

" a " is singly-bound; And

R ²Independently together as following to R¹、R ^3-8Definition; Or

(B)X ¹And X²One of be S, and X¹And X²In another is NR¹⁷；

" a " and " d " respectively is two keys;

" b ", " c ", " e " and " f " respectively are singly-bound;

R ²Be oxo group; And

R ¹⁷Be H or alkyl;

Wherein:

(i)-single-, two-or polyhydroxylated alicyclic group;

-two-or polyhydroxylated aliphatic or aromatic group;

-carbohydrate derivative;

-halogenated alkyl carbonyl;

(ii)COOH、SO ₃H、OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

-SO ₂-alkyl;

-alkyl, optional by one or more OH group replacement;

-CO-alkyl;

-aralkyl;

-COO-alkyl; And

-ether, optional by one or more OH group replacement; And

Wherein Y is not pyridine radicals;

(iv) natural or non-natural amino acid, peptide or peptide derivative;

(v)OSO ₃H、PO ₃H ₂Or OPO₃H ₂；

(vi) Y as defined above, but be not guanidine and quaternary amine;

(vii)(CH ₂) _nNR ¹⁴COR ¹²、(CH ₂) _n’NR ¹⁵SO ₂R ¹³Or SO₂R ¹⁶, R wherein¹²、R ¹³And R¹⁶Respectively doing for oneself to choose wantonly comprises one or more heteroatomic alkyl, and it is optional by one or more OH, NH of being selected from₂, halogen and NO₂Substituting group replace R¹⁴And R¹⁵Be H or alkyl independently of one another, and n and n ' are 0,1,2 or 3 independently of one another;

(x)(CH ₂) _rNH ₂ Wherein r is 0,1,2 or 3;

(xi)(CH ₂) _r’OH; Wherein r ' is 0,1,2 or 3.

49. the formula I compound purposes in for the identification of the analysis of other candidate compounds that can suppress one or more cyclin dependence kinases, GSK and PLK enzyme such as each definition in the claim 1～34.

50. purposes according to claim 49, wherein said analysis are competitive binding analysis.

51. comprising, purposes according to claim 50, wherein said competitive binding analysis will contact and detect any variation of formula I compound and cyclin dependence kinases interaction such as the formula I compound of each definition in the claim 1～34 and cyclin dependence kinases and candidate compound.

52. purposes according to claim 36, wherein said proliferative disease are glomerulonephritis, rheumatoid arthritis, psoriasis or chronic obstructive pulmonary disease.

53. formula I or Ia compound, or its officinal salt is for the preparation of the purposes in the medicine for the treatment of CNS disease.

54. 3 purposes according to claim 5, wherein said CNS disease is Alzheimer's or bipolar disorder.

55. formula I or Ia compound, or its officinal salt for the preparation of the treatment alopecia medicine in purposes.

56. formula I or Ia compound, or its officinal salt, for the preparation of the treatment apoplexy medicine in purposes.

57. according to claim 36, each purposes in 37 or 52～56, wherein compound gives with the amount that is enough to suppress at least a PLK enzyme.

58. 7 purposes according to claim 5, wherein said PLK enzyme is PLK1.

59. according to claim 36, each purposes in 37 or 52～56, wherein compound gives with the amount that is enough to suppress at least a CDK enzyme.

60. 9 purposes according to claim 5, wherein said CDK enzyme is CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 and/or CDK9.

61. according to claim 36, each purposes in 37 or 52～56, wherein compound gives to be enough to the suppressing kinase whose amount of aurora.

62. formula I or Ia compound, or its officinal salt for the preparation of the treatment diabetes medicine in purposes.

63. 2 purposes according to claim 6, wherein said diabetes are type ii diabetes.

64. each purposes in 2 or 63 according to claim 6, wherein compound gives with the amount that is enough to suppress GSK.

65. 4 purposes according to claim 6, wherein compound gives with the amount that is enough to suppress GSK3 β.